System for wireless recording and stimulating bioelectric events

ABSTRACT

Systems and techniques for wireless implantable devices, for example implantable biomedical devices employed for biomodulation. Some embodiments include a biomodulation system including a non-implantable assembly including a source for wireless power transfer and a data communications system, an implantable assembly including a power management module configured to continuously generate one or more operating voltage for the implantable assembly using wireless power transfer from the non-implantable assembly, a control module operably connected to at least one communication channel and at least one stimulation output, the control module including a processor unit to process information sensed via the at least one communication channel and, upon determining a condition exists, to generate an output to trigger the generation of a stimulus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application under 35 U.S.C. § 371and claims the benefit of International Application No.PCT/US2017/037079, filed Jun. 12, 2017, which claims the benefit under35 U.S.C. § 119(e) of U.S. Patent Application No. 62/348,405 entitled“SYSTEM FOR WIRELESS RECORDING AND STIMULATING OF BIOELECTRIC EVENTS”,filed Jun. 10, 2016, which is incorporated herein by reference in itsentirety.

BACKGROUND

This specification relates to systems and techniques for wirelessimplantable devices, for example implantable biomedical devices employedfor biomodulation, including but not limited to neuromodulation(nerves), myomodulation (muscles) and the modulation of any otherbiological functions.

Wireless implantable devices for behavior modulation in subjects, suchas humans, are of great interest in the scientific community. As openloop and feedback based electrical simulators continue to expand inclinical impact, it may be desirable to increase availability of robustfreely behaving data, such as biopotential recordings, from subjects,such as animals, for optimized stimulated parameters and controlalgorithms. It may be desirable to leverage various device-basedtechnologies for implementing biomodulation. A platform of miniatureimplantable technology for human subjects can be utilized as asystematic and object approach to address emerging questions from theclinical community. Additionally, employing implantable wirelesstechnologies may allow for treatment of patients with certain biologicaland physiological disorders (e.g., epilepsy and depression), and for usein increasingly complex chronic behavioral experiments by allowing themto be performed with continuous monitoring.

In addition, advances in wireless powering, ultralow power integratedcircuits (IC) and microprocessors, and IC packaging, may make itdesirable to further incorporate the use of wireless technology forbiomedical research and treatment. Early wireless devices providedseparate and/or distinct functionality, for example either functioningfor biopotential acquisition or for electrical stimulation. In someinstances, powering for these wireless devices was achieved withbatteries or wireless inductive coupling. The emergence of optogeneticsinspired the development of several wireless optical stimulators, eachwith unique features. Nonetheless, use of these devices presented somedrawbacks related to their size, including difficulties beingimplantable comfortably in subjects. In addition, it may be difficult touse a single device in multiple capacities, for example providingbiopotential recording with electrical stimulation, as the early devicesare not configured to support multiple functions.

Vagus nerve stimulation (VNS) is approved by the Food and DrugAdministration (FDA) as an adjunctive treatment option for patients withepilepsy or depression that is resistant to pharmacological therapies.Contemporary VNS treatments are implemented by the surgical implantationof a pacemaker-like device with electrodes that make contact with thevagus nerve in the neck. The implanted battery common to allcontemporary VNS devices accounts for the majority of the device volumeand, as battery functionality declines with age, demands repeatedsurgeries to replace the entire device at intervals spanning years.While research is being performed to develop entirely non-invasivesystems that provide VNS therapy without the need for surgery, thesesystems lack the spatial specificity of implanted devices.

Therefore, it may be desirable to leverage wireless implantable devicesemployable for medical treatments, such as VNS, that provides spatialspecificity and stimulus waveform definition and reliability comparableor superior to contemporary implanted VNS devices while eliminatingactive circuitry and batteries from the implant.

SUMMARY

This document discloses a biomodulation platform for use in humans andanimals. As used herein, “biomodulation” includes but is not necessarilylimited to neuromodulation (nerves), myomodulation (muscles) and themodulation of any other biological functions. This may be accomplishedby: a) monitoring any of a host of parameters induced by thebiomodulation platform, including but not limited to thermal, pressure,other mechanical changes, bioelectric changes, chemical changes (e.g.such as neurotransmitter levels, cytokines, pH), and other biomarkers;and/or b) actuating via the biomodulation platform using any of avariety of suitable techniques (e.g. electrically, optically,mechanically, thermally, ultrasonically, or otherwise) a particularbiological system or outcome of interest. The platform utilizes wirelesspower transfer techniques to transfer power from an external device toan implanted device on a continuous basis, thus enabling further designflexibility in the implantable component design such as a smaller sizeand different and smaller physical configurations.

Generally, the platform enables the implantable components to beimplanted in human and animal research biomodulation anatomicallocations and enables biomodulation applications that would otherwisenot be possible. For example, using platform design features describedin this document, the main implantable component of the platform may beimplanted in anatomical locations within a human not feasible with priorsystems, and/or may be implanted in animal model anatomical locationsnot feasible with prior systems. In addition, the platform enables usescenarios with implantable power requirements that may be unsupportablewith systems using batteries to power implantable components. As such,the platform enables biomodulation research and use scenarios notpreviously possible.

In one aspect, the biomodulation system includes a non-implantableassembly comprising a source for wireless power transfer and a datacommunications system. The biomodulation system further comprises animplantable assembly that includes a power management module configuredto continuously generate operating voltage for the implantable assemblyusing wireless power transfer from the non-implantable assembly. Theimplantable assembly further includes a control module operablyconnected to at least one recording channel and at least one stimulationoutput, the control module including a processor unit to processinformation sensed via the at least one recording channel and, upondetermining a condition exists, to generate an output to trigger thegeneration of a stimulation pulse. In such a biomodulation system, thepower management module generates operating voltage to supply, forexample, analog front-end circuitry for the at least one recordingchannel, the processor unit, a bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and/orstimulation generation circuitry.

In some cases, advantages of the techniques and systems disclosed hereincan include a wireless platform that includes active implants (e.g.,controller implants) and entirely passive implants (e.g., passiveelectrodes) coupled by magnetic fields to an active external generatordevice worn by the patient. Thus, the disclosed system can realizeadvantages of implants employable in various techniques for thetreatment of humans, such as VNS, having a reduced volume and complexityin comparison to some contemporary systems. Moreover, the use ofwireless implantable devices in therapeutic procedures like VNS canrequire reduced surgery, while providing robust forward-compatibilitywith evolving external generators.

The wireless platform also enables chronic freely behaving experimentsfor the study of neurological disease and functional, interventionaltherapies in clinical subjects. Moreover, the disclosed implementationachieves critical design objects such as a miniature footprint forminimal mechanically induced biological impact, modularity for rapidcustomization to a specific need or application, and low powerconsumption to extend operational range and minimize heating forbiological safety. Other benefits are potentially realized inassociation with the system's capabilities to monitor the thermal,pressure, and other mechanical changes, bioelectric changes, chemicalchanges (e.g., neurotransmitter levels, cytokines, pH), and otherbiomarkers induced by the device. Other benefits are potentiallyrealized by the system's capabilities to actuate electrically,optically, mechanically, thermically, ultrasonically, or otherwise, aparticular biological system or outcome of interest. The devices canmonitor electrode impedance due to changes induced by inflammatorycascades or mechanical electrode fatigue. In some cases, commerciallyavailable, or off-the-shelf, components are used in the design topromote access and repeatability. The selection of each integratedcircuit (IC) component can be based on an assessment of performance withrespect to size, thus leveraging the design tradeoff for increasedsuitability for its intended use. Additionally, the disclosed wirelessimplantable devices can have IC packaging, utilizing quad flat no-leadsand a ball grid array packaging, for example, that permits the formfactor of the wireless implantable device to achieve a substantiallyreduced size. The disclosed system can also utilize passive components,thereby providing the benefits a small footprint, for example a 0201,smaller, or larger footprint. In another example, the platform can beused to test and validate preclinical trials and other testingundergoing evaluation.

As a general description, the wireless platform consists of three corehardware units 1) the wireless implantable device, referred tohereinafter as a Bionode assembly, or simply, a Bionode for short; 2) abase station, which can be used to enable wireless bidirectionalcommunication, such as telemetry; and 3) active external generatordevice for wireless powering. The Bionode assembly has two modules: 1)the power module, configured to support power related capabilities suchas to receive the provide continuous energy and 2) the control module toperform command, control, and communication related capacities such asfrom acquired data, for neuromdodulation parameters, and with possiblywireless telemetry to possibly include sensing to track biomarkersand/or signals of interest and stimulation to control biological systemsor outcomes of interest. The modules of the Bionode are capable of beingimplemented as separate PCBs or separate ICs, that are stacked tominimize the footprint, or singly on one PCB or one IC. As an example, aBionode can have a footprint of 7×16×6 mm, another Bionode device has afootprint of 750×750×250 m. Some are larger, some smaller depending onthe application, needs, and sophistication required.

Some embodiments described herein include a biomodulation systemincluding a non-implantable assembly including a source for wirelesspower transfer and a data communications system, an implantable assemblyincluding a power management module configured to continuously generateone or more operating voltage for the implantable assembly usingwireless power transfer from the non-implantable assembly, a controlmodule operably connected to at least one communication channel and atleast one stimulation output, the control module including a processorunit to process information sensed via the at least one communicationchannel and, upon determining a condition exists, to generate an outputto trigger the generation of a stimulus.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The power management module may generate operating voltage tosupply (1) analog front-end circuitry for the at least one communicationchannel, (2) the processor unit, (3) bi-directional telemetry componentto communicate data to and from the non-implantable assembly, and (4)stimulation generation circuitry. The power management module maygenerate two or more different operating voltages including one or morefirst operating voltages at a first voltage level and one or more secondoperating voltages having a second voltage level that is independent ofthe first voltage level, wherein the operating voltages supply (1)different portions of the analog front-end circuitry for the at leastone communication channel, (2) the processor unit, (3) thebi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) the stimulation generation circuitry.The wireless power transfer may be accomplished using magnetic resonancecoupling. The wireless power transfer may be accomplished usingnear-field magnetic inductive coupling. The output to trigger thegeneration of a stimulus may be generated at least in part based on ameasured condition of the subject. The measured condition may bemeasured by an implantable electrode located remote from the implantableassembly. The measured condition may be measured by an electrode of theimplantable assembly. The output may be generated at least in part basedon a closed-loop control algorithm that uses the measured condition ofthe subject as a feedback input. The output may be generated at least inpart by a measured response of the subject to a stimulation delivered byan electrode. The at least one communication channel may be a wiredlead. The at least one communication channel may be a wirelesscommunication channel. The system may include an electrode configured todeliver the stimulus to a subject. The implantable assembly may beimplanted in the chest of a subject. The system may include a leadconfigured for wireless communication with the control module of theimplantable assembly. The control module and lead may be located withina subject remote from one another. The control module may be locatedwithin a chest of a subject, and the implantable electrode may be remotefrom the chest. The electrode may be located within the subject todeliver a stimulus to the bladder. The electrode may be located withinthe subject to deliver a stimulus to the vagus nerve. The electrode maybe located within the subject to deliver a stimulus to a branch of thevagus nerve associated with the gastric system. The electrode may belocated within the subject to deliver a stimulus to the subject'sstomach. The electrode may be located within the subject to deliver astimulus to the cortex. The electrode may be located within the subjectto deliver a stimulus to the brainstem. The electrode may be locatedwithin the subject to deliver a stimulus to the stomach. The electrodemay be located within the subject to deliver a stimulus to the pelvicnerve. The electrode may be located within the subject to deliver astimulus to one or more of: nerves projecting to the esophagus, thelarynx, and the sphincter. The electrode may be configured to measure acondition of the subject. The electrode may include a hormone sensingoptrode. The electrode may include a pressure sensor. The electrode maybe configured to measure bladder pressure. The electrode may include asensor configured to measure a cytokine level. The electrode may includean electrode selected from the group consisting of a single neuronmeasurement electrode, a local field potential (LFP) electrode, anelectroencephalogram (EEG) electrode, electromyography electrode (EMG),and compound nerve action potential electrode (CNAP). The electrode maybe wirelessly powered by the implantable assembly. The electrode may notinclude a power source housed locally within the electrode.

Some embodiments described herein include biomodulation system includingan implantable assembly including: a control module operably connectedto at least one communication channel and at least one stimulationoutput, the control module including a processor unit to processinformation sensed via the at least one communication channel and, upondetermining a condition exists, to generate an output to trigger thegeneration of a stimulus, and a pressure sensor located within a subjectto measure a pressure of the subject's bladder, and a first electrodeconfigured to deliver the stimulus to the subject's pelvic nerve inresponse to the output.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The condition may be at least partially based on a pressuremeasurement of the subject's bladder. The stimulus may be configured togenerate a urinary tract clamping response that prevents urinary voidingof the subject in response to the condition. The implantable assemblymay be configured to remove the stimulus in response to a user input.The system may include a non-implantable assembly including a datacommunications system configured to transmit the user input to theimplantable assembly. The system may include a non-implantable assemblyincluding a data communications system. The non-implantable assembly mayinclude a source for wireless power transfer to a power managementmodule of the implantable assembly. The wireless power transfer may beaccomplished using magnetic resonance coupling. The wireless powertransfer is accomplished using far-field radio frequency (RF) powering.The implantable assembly may include a power management moduleconfigured to continuously generate operating voltage or voltages forthe implantable assembly. The power management module may generateoperating voltage to supply (1) analog front-end circuitry for the atleast one communication channel, (2) the processor unit, (3)bi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) stimulation generation circuitry. Thepower management module may generate two or more different operatingvoltages including one or more first operating voltages at a firstvoltage level and one or more second operating voltages having a secondvoltage level that is independent of the first voltage level, whereinthe operating voltages supply (1) different portions of the analogfront-end circuitry for the at least one communication channel, (2) theprocessor unit, (3) the bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and (4) thestimulation generation circuitry. The pressure sensor may include apiezoresistive differential pressure sensor. The pressure sensor mayinclude a receiver powering coil. The pressure sensor may not include abattery. The pressure sensor may include an active transmitter.

Some embodiments described herein include a method of biomodulation forreducing urinary incontinence symptoms, including measuring a bladderpressure by an electrode including a pressure sensor, wirelesslytransmitting the bladder pressure to a control module of an implantableassembly, the control module implanted within the subject remote fromthe electrode and operably connected to at least one communicationchannel configured to receive the bladder pressure measurement, thecontrol module including a processor unit to process bladder pressuresensed via the at least one communication channel, determining acondition exists based at least in part on the bladder pressuremeasurement, and delivering an electrical stimulation configured togenerate a urinary tract clamping response in the subject to preventurinary voiding.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. Delivering an electrical stimulation may include delivering anelectrical stimulation to the subject's pelvic nerve. The method mayinclude wirelessly transferring the bladder pressure measurement to anon-implantable assembly, processing the bladder pressure measurement bythe non-implantable assembly, and transmitting a command to theimplantable assembly to generate an output to deliver the electricalstimulation. The method may include transferring power wirelessly to apower management module of the implantable assembly. Transferring powermay include charging a rechargeable battery of the implantable assembly.The method may include transferring power wirelessly to the electrode,the wireless power transfer sufficient for the electrode to generate theelectrical stimulation. The at least one communication channel mayinclude a wired lead. The at least one communication channel may includea wireless communication channel. The pressure sensor may include apiezoresistive differential pressure sensor. The pressure sensor mayinclude a receiver powering coil. The pressure sensor may not include abattery. The pressure sensor may include an active transmitter.

Some embodiments described herein include a method of biomodulation,including measuring a patient condition by an implanted electrode,communicating the measurement to a control module of an implantedassembly, the implanted assembly located within the subject remote fromthe electrode, the control module having at least one stimulationoutput, the control module including a processor unit to process themeasurement, generating an output to trigger the generation of astimulus, and delivering a first stimulus according to a first set ofstimulation parameters in response to the output, the first set ofstimulation parameters determined based at least in part on themeasurement of the patient condition.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. The method may include delivering a second electricalstimulation according to a second set of stimulation parametersdifferent than the first set of stimulation parameters. The first set ofstimulation parameters and the second set of stimulation parameters maybe calculated to deliver a constant dose of neural activity. The firstelectrical stimulation and the second electrical stimulation may bedelivered at a predetermined interval. Measuring the patient conditionmay include measuring the patient condition in response to a priorelectrical stimulation delivered before the first electricalstimulation.

Some embodiments described herein include a biomodulation systemincluding an implantable assembly including a control module operablyconnected to at least one communication channel and at least onestimulation output, the control module including a processor unit toprocess information sensed via the at least one communication channeland, upon determining a condition exists, to generate an output totrigger the generation of a stimulus, a sensor located within a subjectto obtain a condition measurement of a physiological pathway of thesubject, the condition measurement a cytokine level, and a firstelectrode configured to deliver the stimulus to the subject based atleast on part on the condition measurement, the stimulus configured toaffect an inflammation reflex when a seizure occurs.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The sensor may include an optical sensor configured to measurethe cytokine level. The first electrode may be configured to deliver thestimulus to a location selected from the group consisting of the brainstem, cortex, and vagus nerve. The electrical stimulation may includedeep brain stimulation (DBS). The system may include a non-implantableassembly including a data communications system configured to transmitthe user input to the implantable assembly. The non-implantable assemblymay include a source for wireless power transfer to a power managementmodule of the implantable assembly. The wireless power transfer may beaccomplished using magnetic resonance coupling. The wireless powertransfer may be accomplished using near-field magnetic inductivecoupling. The implantable assembly may include a power management moduleconfigured to continuously generate operating voltage for theimplantable assembly. The power management module may generate operatingvoltage to supply (1) analog front-end circuitry for the at least onecommunication channel, (2) the processor unit, (3) bi-directionaltelemetry component to communicate data to and from the non-implantableassembly, and (4) stimulation generation circuitry. The power managementmodule may generate two or more different operating voltages includingone or more first operating voltages at a first voltage level and one ormore second operating voltages having a second voltage level that isindependent of the first voltage level, wherein the operating voltagessupply (1) different portions of the analog front-end circuitry for theat least one communication channel, (2) the processor unit, (3) thebi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) the stimulation generation circuitry.

Some embodiments described herein include a method of biomodulation forreducing symptoms of epilepsy, including monitoring a physiologicalpathway by an electrode to obtain a condition measurement including acytokine level, wirelessly transmitting the condition measurement to acontrol module of an implantable assembly, the control module implantedwithin the subject remote from the electrode and operably connected toat least one communication channel configured to receive the conditionmeasurement, the control module including a processor unit to processthe condition measurement sensed via the at least one communicationchannel, determining a condition exists based at least in part on thecondition measurement, and delivering an electrical stimulationconfigured to affect an inflammation reflex when a seizure occurs.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. The electrode may include an optical sensor configured tomeasure the cytokine level. Delivering an electrical stimulation mayinclude delivering an electrical stimulation to a location selected fromthe group consisting of the brain stem, cortex, and vagus nerve. Themethod may include wirelessly transferring the condition measurement toa non-implantable assembly, processing the condition measurement by thenon-implantable assembly, and transmitting a command to the implantableassembly to generate an output to deliver the electrical stimulation.The method may include transferring power wirelessly to a powermanagement module of the implantable assembly. Transferring power mayinclude charging a rechargeable battery of the implantable assembly. Themethod may include transferring power wirelessly to the electrode, thewireless power transfer sufficient for the electrode to generate theelectrical stimulation. The at least one communication channel mayinclude a wired lead. The at least one communication channel may includea wireless communication channel. The electrical stimulation may includedeep brain stimulation (DBS).

Some embodiments described herein include a biomodulation systemincluding an implantable assembly including a control module operablyconnected to at least one communication channel and at least onestimulation output, the control module including a processor unit toprocess information sensed via the at least one communication channeland, upon determining a condition exists, to generate an output totrigger the generation of a stimulus, one or more sensors located withina subject to obtain a pH level, a temperature, and a respiratorycondition, and a first electrode configured to deliver the stimulus tothe subject based at least in part on one or more of the pH level,temperature, and respiratory condition, wherein the stimulus isconfigured to affect a reflex when a seizure occurs.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The first electrode may be configured to deliver the stimulusto a location selected from the group consisting of the brain stem,cortex, vagus nerve, sympathetic nerves, upper esophageal sphincter, andlarynx. The electrical stimulation may be deep brain stimulation (DBS).The system may include including a non-implantable assembly including adata communications system configured to transmit the user input to theimplantable assembly. The non-implantable assembly may include a sourcefor wireless power transfer to a power management module of theimplantable assembly. The wireless power transfer may be accomplishedusing magnetic resonance coupling. The wireless power transfer may beaccomplished using near-field magnetic inductive coupling. Theimplantable assembly may include a power management module configured tocontinuously generate operating voltage for the implantable assembly.The power management module may generate operating voltage to supply (1)analog front-end circuitry for the at least one communication channel,(2) the processor unit, (3) bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and (4)stimulation generation circuitry. The power management module maygenerate two or more different operating voltages including one or morefirst operating voltages at a first voltage level and one or more secondoperating voltages having a second voltage level that is independent ofthe first voltage level, wherein the operating voltages supply (1)different portions of the analog front-end circuitry for the at leastone communication channel, (2) the processor unit, (3) thebi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) the stimulation generation circuitry,and wherein the second operating voltage supplies the stimulationgeneration circuitry.

Some embodiments described herein include a method of biomodulation forreducing symptoms of epilepsy, including, monitoring a physiologicalpathway by an electrode to obtain a condition measurement including a pHlevel, temperature, and respiratory level, wirelessly transmitting thecondition measurement to a control module of an implantable assembly,the control module implanted within the subject remote from theelectrode and operably connected to at least one communication channelconfigured to receive the condition measurement, the control moduleincluding a processor unit to process the condition measurement sensedvia the at least one communication channel, determining a conditionexists based at least in part on the condition measurement, anddelivering an electrical stimulation configured to affect a reflex whena seizure occurs.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. Delivering an electrical stimulation may include delivering anelectrical stimulation to a location selected from the group consistingof the brain stem, cortex, vagus nerve, sympathetic nerves, upperesophageal sphincter, and larynx. The method may include wirelesslytransferring the condition measurement to a non-implantable assembly,processing the condition measurement by the non-implantable assembly,and transmitting a command to the implantable assembly to generate anoutput to deliver the electrical stimulation. The method may includetransferring power wirelessly to a power management module of theimplantable assembly. Transferring power may include charging arechargeable battery of the implantable assembly. The method may includetransferring power wirelessly to the electrode, the wireless powertransfer sufficient for the electrode to generate the electricalstimulation. The at least one communication channel may include a wiredlead. The at least one communication channel may include a wirelesscommunication channel. The electrical stimulation may include deep brainstimulation (DBS).

Some embodiments described herein include a biomodulation systemincluding an implantable assembly including a control module operablyconnected to at least one communication channel and at least onestimulation output, the control module including a processor unit toprocess information sensed via the at least one communication channeland, upon determining a condition exists, to generate an output totrigger the generation of a stimulus, one or more sensors located withina subject configured to obtain a cytokine level, and a first electrodeconfigured to deliver the stimulus to the subject based at least in parton the cytokine level, the stimulus configured to cause a vagallymediated reduction in lymphocyte release from post-synaptic cites of thevagus nerve in the gastrointestinal tract.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The first electrode may be configured to deliver the stimulusto the vagus nerve. The system may include a non-implantable assemblyincluding a data communications system configured to transmit the userinput to the implantable assembly. The non-implantable assembly mayinclude a source for wireless power transfer to a power managementmodule of the implantable assembly. The wireless power transfer may beaccomplished using magnetic resonance coupling. The wireless powertransfer may be accomplished using near-field magnetic inductivecoupling. The implantable assembly may include a power management moduleconfigured to continuously generate operating voltage for theimplantable assembly. The power management module may generate operatingvoltage to supply (1) analog front-end circuitry for the at least onecommunication channel, (2) the processor unit, (3) bi-directionaltelemetry component to communicate data to and from the non-implantableassembly, and (4) stimulation generation circuitry. The power managementmodule may generate two or more different operating voltages includingone or more first operating voltages at a first voltage level and one ormore second operating voltages having a second voltage level that isindependent of the first voltage level, wherein the operating voltagessupply (1) different portions of the analog front-end circuitry for theat least one communication channel, (2) the processor unit, (3) thebi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) the stimulation generation circuitry,and wherein the second operating voltage supplies the stimulationgeneration circuitry.

Some embodiments described herein include a method of biomodulation forreducing symptoms of inflammation, including monitoring a physiologicalpathway by an electrode to obtain a condition measurement that includesa cytokine level, wirelessly transmitting the condition measurement to acontrol module of an implantable assembly, the control module implantedwithin the subject remote from the electrode and operably connected toat least one communication channel configured to receive the conditionmeasurement, the control module including a processor unit to processthe condition measurement sensed via the at least one communicationchannel, determining a condition exists based at least in part on thecondition measurement, and delivering an electrical stimulation of thevagus nerve configured to cause a vagally mediated reduction inlymphocyte release from post-synaptic cites of the vagus nerve in thegastrointestinal tract.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. The method may include wirelessly transferring the conditionmeasurement to a non-implantable assembly, processing the conditionmeasurement by the non-implantable assembly, and transmitting a commandto the implantable assembly to generate an output to deliver theelectrical stimulation. The method may include transferring powerwirelessly to a power management module of the implantable assembly.Transferring power may include charging a rechargeable battery of theimplantable assembly. The method may include transferring powerwirelessly to the electrode, the wireless power transfer sufficient forthe electrode to generate the electrical stimulation. The at least onecommunication channel may include a wired lead. The at least onecommunication channel may include a wireless communication channel.

Some embodiments described herein include a biomodulation systemincluding an implantable assembly including a control module operablyconnected to at least one communication channel and at least onestimulation output, the control module including a processor unit toprocess information sensed via the at least one communication channeland, upon determining a condition exists, to generate an output totrigger the generation of a stimulus and one or more electrodesconfigured to deliver the stimulus to the subject, the stimulusconfigured to cause reversible inactivation of the nucleus accumbensshell (AcbSh).

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. The system may include one or more electrodes configured todeliver the stimulation to a location selected from the group consistingof midbrain dopaminergic system, such as the ventral tegmental area,nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala. Thesystem may include a non-implantable assembly including a datacommunications system configured to transmit the user input to theimplantable assembly. The non-implantable assembly may include a sourcefor wireless power transfer to a power management module of theimplantable assembly. The wireless power transfer may be accomplishedusing magnetic resonance coupling. The wireless power transfer may beaccomplished using near-field magnetic inductive coupling. Theimplantable assembly may include power management module configured tocontinuously generate operating voltage for the implantable assembly.The power management module may generate operating voltage to supply (1)analog front-end circuitry for the at least one communication channel,(2) the processor unit, (3) bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and (4)stimulation generation circuitry. The power management module maygenerate two or more different operating voltages including one or morefirst operating voltages at a first voltage level and one or more secondoperating voltages having a second voltage level that is independent ofthe first voltage level, wherein the operating voltages supply (1)different portions of the analog front-end circuitry for the at leastone communication channel, (2) the processor unit, (3) thebi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) the stimulation generation circuitry,and wherein the second operating voltage supplies the stimulationgeneration circuitry. The system may include an electrode configured tomonitor the subject's cortex in response to the stimulation.

Some embodiments described herein include a method of biomodulation forreducing symptoms of alcoholism, including, monitoring a physiologicalpathway by an electrode to obtain a condition measurement, wirelesslytransmitting the condition measurement to a control module of animplantable assembly, the control module implanted within the subjectremote from the electrode and operably connected to at least onecommunication channel configured to receive the condition measurement,the control module including a processor unit to process the conditionmeasurement sensed via the at least one communication channel, anddelivering an electrical stimulation based at least in part on thecondition measurement, wherein the electrical stimulation includes deepbrain stimulation configured to cause reversible inactivation of thenucleus accumbens shell (AcbSh).

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. Monitoring a physiological pathway may include monitoring thecortex. The method may include wirelessly transferring the conditionmeasurement to a non-implantable assembly, processing the conditionmeasurement by the non-implantable assembly, and transmitting a commandto the implantable assembly to generate an output to deliver theelectrical stimulation. The method may include transferring powerwirelessly to a power management module of the implantable assembly.Transferring power may include charging a rechargeable battery of theimplantable assembly. The method may include transferring powerwirelessly to the electrode, the wireless power transfer sufficient forthe electrode to generate the electrical stimulation. The at least onecommunication channel may include a wired lead. The at least onecommunication channel may include a wireless communication channel.

Some embodiments described herein include a biomodulation systemincluding an implantable assembly including a control module operablyconnected to at least one communication channel and at least onestimulation output, the control module including a processor unit toprocess information sensed via the at least one communication channeland, upon determining a condition exists, to generate an output totrigger the generation of a stimulus; and one or more electrodesconfigured to deliver the stimulus to a subject's cortex, the stimulusconfigured to deliver deep brain stimulation to the subject's cortex.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The system may include a non-implantable assembly including adata communications system configured to transmit the user input to theimplantable assembly. The non-implantable assembly may include a sourcefor wireless power transfer to a power management module of theimplantable assembly. The wireless power transfer may be accomplishedusing magnetic resonance coupling. The wireless power transfer may beaccomplished using near-field magnetic inductive coupling. Theimplantable assembly may include a power management module configured tocontinuously generate operating voltage for the implantable assembly.The power management module may generate operating voltage to supply (1)analog front-end circuitry for the at least one communication channel,(2) the processor unit, (3) bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and (4)stimulation generation circuitry. The power management module maygenerate two or more different operating voltages including one or morefirst operating voltages at a first voltage level and one or more secondoperating voltages having a second voltage level that is independent ofthe first voltage level, wherein the operating voltages supply (1)different portions of the analog front-end circuitry for the at leastone communication channel, (2) the processor unit, (3) thebi-directional telemetry component to communicate data to and from thenon-implantable assembly, and (4) the stimulation generation circuitry,and wherein the second operating voltage supplies the stimulationgeneration circuitry. The system may include an electrode configured tomonitor the subject's cortex in response to the stimulation.

Some embodiments described herein include a method of biomodulation forreducing symptoms of alcoholism, including monitoring a physiologicalpathway by an electrode to obtain a condition measurement, wirelesslytransmitting the condition measurement to a control module of animplantable assembly, the control module implanted within the subjectremote from the electrode and operably connected to at least onecommunication channel configured to receive the condition measurement,the control module including a processor unit to process the conditionmeasurement sensed via the at least one communication channel, anddelivering an electrical stimulation based at least in part on thecondition measurement, wherein the electrical stimulation includes deepbrain stimulation of the cortex.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. Monitoring a physiological pathway may include monitoring thecortex. The method may include wirelessly transferring the conditionmeasurement to a non-implantable assembly, processing the conditionmeasurement by the non-implantable assembly, and transmitting a commandto the implantable assembly to generate an output to deliver theelectrical stimulation. The method may include transferring powerwirelessly to a power management module of the implantable assembly.Transferring power may include charging a rechargeable battery of theimplantable assembly. The method may include transferring powerwirelessly to the electrode, the wireless power transfer sufficient forthe electrode to generate the electrical stimulation. The at least onecommunication channel may include a wired lead. The at least onecommunication channel may include a wireless communication channel.

Some embodiments described herein include a biomodulation systemincluding an implantable assembly including a control module operablyconnected to at least one communication channel and at least onestimulation output, the control module including a processor unit toprocess information sensed via the at least one communication channeland, upon determining a condition exists, to generate an output totrigger the generation of a stimulus, a sensor located within a subjectto obtain a condition measurement of a physiological pathway of thesubject, the condition measurement including a hormone level, and afirst electrode configured to deliver the stimulus to the subject basedat least on part on the condition measurement, the stimulus configuredto affect a gastric condition.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The sensor may include an optical sensor configured to measurethe hormone level. The hormone level may be selected from the groupconsisting of ghrelin, PYY, somatostatin, gastrin, nesfatin, leptin and5-HT (e.g. in the stomach), and/or CCK, secretin, 5-HT, GIP, GLP-1, PYYand neurotensin. The first electrode may be configured to deliver thestimulus to a location selected from the group consisting of a branch ofthe vagus nerve associated with the stomach, a branch of the vagus nerveassociated with stomach sphincters, a distal esophagus, the stomachmuscle, and a proximal duodenum. The system may include anon-implantable assembly including a data communications systemconfigured to transmit the user input to the implantable assembly. Thenon-implantable assembly may include a source for wireless powertransfer to a power management module of the implantable assembly. Thewireless power transfer may be accomplished using magnetic resonancecoupling. The wireless power transfer may be accomplished usingnear-field magnetic inductive coupling. The implantable assembly mayinclude a power management module configured to continuously generateoperating voltage for the implantable assembly. The power managementmodule may generate operating voltage to supply (1) analog front-endcircuitry for the at least one communication channel, (2) the processorunit, (3) bi-directional telemetry component to communicate data to andfrom the non-implantable assembly, and (4) stimulation generationcircuitry. The power management module may generate two or moredifferent operating voltages including one or more first operatingvoltages at a first voltage level and one or more second operatingvoltages having a second voltage level that is independent of the firstvoltage level, wherein the operating voltages supply (1) differentportions of the analog front-end circuitry for the at least onecommunication channel, (2) the processor unit, (3) the bi-directionaltelemetry component to communicate data to and from the non-implantableassembly, and (4) the stimulation generation circuitry, and wherein thesecond operating voltage supplies the stimulation generation circuitry.

Some embodiments described herein include a method of biomodulation forreducing symptoms of a gastric disorder, including monitoring aphysiological pathway by an electrode to obtain a condition measurementincluding a hormone level, wirelessly transmitting the conditionmeasurement to a control module of an implantable assembly, the controlmodule implanted within the subject remote from the electrode andoperably connected to at least one communication channel configured toreceive the condition measurement, the control module including aprocessor unit to process the condition measurement sensed via the atleast one communication channel, determining a condition exists based atleast in part on the condition measurement, and delivering an electricalstimulation configured to affect a gastric condition.

In some implementations, the method including include one or more of thefollowing features, including each combination and subcombination offeatures. The electrode may include an optical sensor configured tomeasure the hormone level. The hormone level may be selected from thegroup consisting of ghrelin, PYY, somatostatin, gastrin, nesfatin,leptin and 5-HT (e.g. in the stomach), and/or CCK, secretin, 5-HT, GIP,GLP-1, PYY and neurotensin. Delivering an electrical stimulation mayinclude delivering an electrical stimulation to a location selected fromthe group consisting of a branch of the vagus nerve associated with thestomach, a branch of the vagus nerve associated with stomach sphincters,a distal esophagus, the stomach muscle, and a proximal duodenum. Themethod may include wirelessly transferring the condition measurement toa non-implantable assembly, processing the condition measurement by thenon-implantable assembly, and transmitting a command to the implantableassembly to generate an output to deliver the electrical stimulation.The method may include transferring power wirelessly to a powermanagement module of the implantable assembly. Transferring power mayinclude charging a rechargeable battery of the implantable assembly. Themethod may include transferring power wirelessly to the electrode, thewireless power transfer sufficient for the electrode to generate theelectrical stimulation. The at least one communication channel mayinclude a wired lead. The at least one communication channel may includea wireless communication channel.

Some embodiments described herein include a biomodulation system,including a non-implantable means for wireless power transfer and datacommunications, and an implantable means for generating operatingvoltage for an implantable assembly using wireless power transfer, andmeans for receiving an measurement related to a patient condition andgenerating an output to trigger the generation of a stimulus based atleast in part on the measurement.

Some embodiments described herein include a biomodulation systemincluding a resonant cavity including a source for wireless powertransfer, an implantable assembly including, a power management moduleconfigured to continuously generate one or more operating voltage forthe implantable assembly using wireless power transfer from thenon-implantable assembly, and a control module operably connected to atleast one communication channel and at least one stimulation output, thecontrol module including a processor unit to process information sensedvia the at least one communication channel and, upon determining acondition exists, to generate an output to trigger the generation of astimulus.

In some implementations, the system including include one or more of thefollowing features, including each combination and subcombination offeatures. The implantable assembly may be inserted into a subject thatis located within the resonant cavity. The subject may be a non-humanmammal. The non-human mammal may be a rodent. The resonant cavity mayinclude a cage for the non-human mammal, with the walls of the cageincluding antennae for the wireless power transfer. The biomodulationsystem may be configured for use in pre-clinical testing.

The biomodulation systems and methods described herein may includewireless power transfer that serves to charge or re-charge arechargeable power supply. The biomodulation systems and methodsdescribed herein may include wireless power transfer accomplished usingfar-field radio frequency (RF) powering. The biomodulation systems andmethods described herein may be used with a patient that is a human. Thebiomodulation systems and methods described herein may be used with apatient that is a non-human mammal.

The details of one or more embodiments of the subject matter describedin this specification are set forth in the accompanying drawings and thedescription below. Other features, aspects, and advantages of theinvention will become apparent from the description, the drawings, andthe claims.

DRAWING DESCRIPTIONS

FIGS. 1A-1B shows a diagram of an example of the wireless platformsystem, including a wireless implantable device, for implementingwireless recording and stimulating of bioelectric events.

FIGS. 2A-2B show a top and bottom view, respectively, of an example of amain board for the wireless implantable device for implementing thedisclosed techniques.

FIGS. 2C-2D show an example of a wireless implantable device forimplementing the disclosed techniques.

FIG. 3A shows a diagram of an example for circuitry implementing ananalog front-end (AFE) aspect of the wireless implantable device forimplementing the disclosed techniques.

FIG. 3B shows an example of circuitry for implementing a constantcurrent stimulation aspect of the wireless implantable device.

FIG. 4 shows an example graph displaying current-controlled, biphasicoutput measured from the stimulator outputs aspect of the wirelessimplantable device.

FIG. 5 shows an example of a graph displaying root-mean-square (RMS)voltage measured employing the electrode impedance measurementcapabilities aspect of the wireless implantable device.

FIG. 6 shows an example of a graph displaying plotted points oftemperature sensor measurements and curve of thermocouple change.

FIG. 7 shows an example of a format for a data packet structure, used inimplementing a wireless communication protocol.

FIG. 8 shows a diagram depicting an example of the communication pathbetween components of the wireless platform system.

FIG. 9 shows a diagram of an example of circuitry implementing impedancematching aspects of the wireless implantable device.

FIG. 10 shows an example of the packaging process of a wirelessimplantable device, via a cross-sectional view.

FIG. 11 is a flow chart of an exemplary method of implanting a module(implantable Bionode capsule) in a subject is shown.

FIG. 12 is a flow chart of an exemplary method of calibrating a moduleis shown.

FIG. 13 is a flow chart of an exemplary method of delivering astimulation to a subject is shown using an implanted module.

FIG. 14 is a flow chart of an exemplary method of operation of thesystem including an implantable module and an external base station thatobtains patient input is shown.

FIGS. 15 and 16 depict an example system in which an implantable systemis configured for the treatment of epilepsy in a patient.

FIGS. 17A-C depict the anatomy and projections of the vagus nerve, andthe implant locations of for the system.

FIG. 18 depicts a cardiocentric view of the autonomic neuronal hierarchythat coordinates regional cardiac indexes as they related to the CNS.

FIG. 19 shows a block diagram of the possible feature extraction schemesthat can be applied to implantable medical devices.

FIG. 20 depicts an example system in which an implantable system isconfigured for the treatment of epilepsy in a patient.

FIG. 21 depicts an example system in which an implantable system isconfigured for the treatment of urinary incontinence in a patient.

FIG. 22 shows the anatomical relationship between pelvic nerve andbladder and the localization of sensors and electrodes placed in thebladder, external urethral sphincter and pelvic nerve.

FIG. 23 shows example silver hook electrode assemblies used forstimulation and recording from the pelvic nerve.

FIG. 24 shows an example of cuff electrodes used for stimulation andrecording from the pelvic nerve.

FIG. 25 depicts example testing results of pelvic nerve stimulation.

FIG. 26 depicts example testing results from monitoring the whole pelvicnerve bundle and portions thereof.

FIG. 27 depicts example testing results from monitoring portions of thewhole pelvic nerve bundle.

FIG. 28 depicts example testing results correlating bladder pressure andnerve activity.

FIG. 29 depicts example testing results from stimulation of the pelvicnerve using high frequency charge balanced alternating current as itrelates to bladder pressure signaling an imminent void.

FIG. 30 depicts example testing results showing the frequency dependencebetween the effect of pelvic nerve stimulation on voiding.

FIG. 31 depicts example results of an experiment testing a mechanismunderlying pelvic nerve-evoked suppression of voiding.

FIG. 32 depicts an example results of experiments testing ligating thepelvic nerve distal to the stimulating electrode.

FIG. 33 depicts an example system in which an implantable system isconfigured for the treatment of inflammation reflex in a patient.

FIG. 34 depicts an example system in which the control device providessimultaneous stimulation and readings on a nerve as part of a closedloop control algorithm.

FIG. 35 depicts an example system in which an implantable system isconfigured for the treatment of alcoholism in a patient.

FIG. 36 depicts an example implantable system configured for preclinicaltrials related to subjects with Parkinson's disease in a patient.

FIG. 37 depicts an example system to treat gastric disorders.

FIG. 38 depicts an example system in which an implantable system isconfigured for the treatment of addiction in a patient.

FIGS. 39A-B are conceptual diagrams of the target implant location andthe readout ASIC: (A) Bladder pressure monitor system. (B) Readout fullsystem implant comprises a readout ASIC, an antenna and a powering coil.

FIG. 40 is a block diagram of the pressure-sensing system on a chip(SoC).

FIG. 41 is a block diagram of energy harvesting (EH) and powermanagement subsystems.

FIG. 42 is a schematic diagram of the bandgap reference to generatepseudo-differential reference voltages and bias currents for the SoCchip.

FIG. 43 is a schematic diagram of one of the four voltage regulators andtheir supply domains.

FIG. 44 is a concept diagram of the implemented R-F converter.

FIG. 45 is a schematic diagram of a conventional R-I converter.

FIG. 46 is a schematic diagram of first differential R-I (R-I1)converter.

FIG. 47 is a schematic diagram of second differential R-I (R-I2)converter.

FIG. 48 is a schematic diagram of the ring oscillator, providing I-Fconversion.

FIG. 49 is a digital Core: (a) Block diagram. (b) F-D converter. (c)Block diagram of encoder (ENC). (d) State diagram of ENC.

FIG. 50 is a timing diagram of digital core and the packet structure.

FIG. 51 is a schematic diagram of the 2.45 GHz ISM band transmitter,comprising a voltage-controlled power oscillator (VCPO) and an off-chiploop antenna.

FIG. 52 is an equivalent lumped circuit model of an electrically smallloop antenna. The antenna can be modeled as a series combination of aninductor (LA) and a resistor (RA). CSRF models the self resonancefrequency of the loop.

FIG. 53 is a simulated antenna radiation pattern: (a) on a FR-4 board(air). (b) gold trace on a 20 μm thick parylene substrate with a 20 μmparylene coating.

FIG. 54 is a simplified schematic diagram of 5-bit DAC, implemented byMIM capacitors to tune the resonance frequency of the LC tank.

FIG. 55 illustrates a micro-photograph of the implemented chip.

FIG. 56 illustrates a measured and simulated current for the R-I1Converter.

FIG. 57 illustrates a) a Pseudo-differential reference voltage acrossthe sense resistors terminals in R-I2 converter, and (b) 100 mVreference voltage across the sensor resistors in R-I1 converter.

FIG. 58 illustrates a measured TX power spectrum, OOK modulated by thePRBS at various data rates.

FIG. 59 illustrates a measured TX power spectrum, FSK modulated by 1Mbps PRBS.

FIG. 60 illustrates a measured waveforms and data packet for the fullsystem.

FIG. 61 illustrates measured data packets that correspond to: a) Basefrequency, b) Sensor frequency and c) Difference between two sensorfrequencies.

FIG. 62 illustrates measured change in the sensor frequency withpressure, where base frequency remains constant with applied pressure.

FIG. 63 illustrates measured difference in sensor resistances (RS1-RS2)and integral non-linearity.

FIG. 64 illustrates measured sensitivity of the chip with number ofaveraged data samples (or conversion time)

FIG. 65 illustrates measured power spectrum of the received data.

FIG. 66 illustrates received RF data and corresponding digital packets.

FIG. 67 illustrates a wirelessly measured noise floor for resistancesensing.

FIG. 68 illustrates a wirelessly measured noise histogram for resistancesensing.

FIG. 69 illustrates a pressure measurement with time.

FIG. 70 illustrates measured temperature variation in sensing and basefrequencies.

FIG. 71 illustrates in-vivo experiments including: a) Experimentalsetup, and b) Bladder pressure recording.

FIG. 72 is a cavity resonator forming part of the wireless powertransfer system for use in pre-clinical biomedical research involvingnon-human mammals (such as a rat) with a Bionode implanted.

FIG. 73 is a constructed cavity resonator and fully assembled devicewith Bionode microelectronics platform, power management board, andreceive coil assembly according to the present disclosure.

FIG. 74 is a chart comparing the system performance when employingwireless power transfer with the resonant cavity system relative toother types of wireless power transfer.

Like reference, numbers and designations in the various drawingsindicate like elements.

DETAILED DESCRIPTION

Disclosed herein are techniques and systems related to a biomodulationsystem including a main wireless implantable device, referred to hereinas a Bionode assembly or Bionode for short, which in someimplementations is powered without an implanted battery or implantedactive circuitry, thereby allowing a design to have minimal possiblevolume, complexity, and sensitivity to variations in operatingconditions. Additionally, the biomodulation system (which also may bereferred to as the Bionode platform) achieves these advantages, whileproviding the spatial specificity and stimulation waveform definitionprovided by some existing biomodulation systems.

The biomodulation system utilizing the Bionode can provide distinctadvantages over some existing technologies, by realizing a high level offunctionality, adaptability, and compatibility (e.g., with externaltesting environment). The operating conditions for the implantableBionode can be configurable through its use of reprogrammable firmware,bidirectional communication (e.g., enabling immediate updates), andselectable hardware components. The system can also be enabled withfunctions beyond biological recording and stimulating, for instancedevice temperature sensing and electrode impedance measurements, (bothof which provide valuable feedback to the user once the device isimplanted and inaccessible). Moreover, the integrated stimulator of theBionode can be used as an instrument for calibration. As discussedthroughout, the Bionode platform implements extensive functionality andmulti-tasking ability. Thus, the Bionode platform has utility as apossibly battery-less, fully implantable wireless solution in thebiomedical field, for instance being employable in a wide range ofelectrophysiological and behavior treatments and studies.

FIG. 1A shows an embodiment of a biomodulation platform system 100including an implantable wireless device employing wireless powertransfer. The wireless platform system 100 is designed for monitoringand actuating biological sites, and therefore enabling targeted andcontrolled activation of the biological pathway of a desired therapy ofa patient 190, shown in FIG. 1A as a human. It should be appreciatedthat while applicable to human patients, as illustrated in FIG. 1A, thewireless platform system 100 can be utilized in treatments andbiomedical research involving non-human patients, such as other mammals.For example, the system 100 can be employed in chronic behavioralexperiments performed in rodents. The wireless platform system 100 isconfigured to perform biomodulation in a human patient 190, and can beapplicable to a wide range of medical conditions including, but notlimited to: epilepsy; glaucoma; inflammation; incontinence;gastroparesis; addiction; alcoholism; Parkinson's (e.g., preclinicaltrials); and the like. Various embodiments of the wireless platformsystem 100 that are each configured for suitable use in the specializedtreatment of a respective condition are addressed in detail herein.

FIG. 1A shows the wireless platform system 100 includes an implantableassembly, namely, a Bionode assembly 170, or simply, the Bionode; and anon-implantable, and in many use cases wearable, base station assembly140. The system 100 utilizes wireless power transfer (WPT) 195 totransfer power wirelessly from the non-implantable base station 140 tothe implantable Bionode 170, to provide operating voltage for theBionode 170 on a continuous basis. The system 100 can be used forvarious treatments by surgical implantation with electrodes 175operatively connected to the Bionode 170 that make contact with thedesired biological site of the patient 190, while excluding the use ofan implanted battery. Thus, the smaller size and implantable nature ofthe Bionode 170 supports precise targeting, dosing, and monitoring ofneural activation within the patient 190. FIG. 1A also illustratesvarious sub-elements of the Bionode 170 and the base station 140devices. The Bionode 170 is shown as including the power managementboard 101 and main board 120, configured for performing the capabilitiesof the implantable device, as discussed in detail herein. The basestation 140 is shown as including a power amplifier 141 utilized in thewireless power transfer process; board computer 142 (e.g., computingplatform with modifiable hardware and software modules, such asRaspberry Pi platforms); and microcontroller unit (MCU) 145. Thesub-elements for the Bionode 170 and the base station 140 are discussedin detail in reference to FIG. 1B below.

Electrodes 175 are electrical conductors used to make contact with anonmetallic part of a circuit, such as human tissue, which can beconfigured for performing recording of bioelectric events in accordancewith the disclosed techniques. In some embodiments, the electrodes 175can be optionally implemented as components of the Bionode 170.According to this embodiment, the electrodes 175 have a wired couplingto the main board 101 of the Bionode 170 via a feedthrough board.

In accordance with the disclosed techniques, driving the Bionode 170,without an internal battery, involves the use of a wireless poweringmechanism illustrated generally as 195. In an embodiment, the wirelesspowering aspects of the system 100 are embodied in part in anon-implanted base station component 140 that can be worn comfortably bythe patient. Wireless power transfer 195 from the base station 140 tothe implantable Bionode 170 may, in some embodiments, be accomplishedusing enhanced magnetic inductive coupling techniques utilizing metalcoils on the power management board 101 of the Bionode 170 to a magneticfield generated by the base station 195. According to an implementation,wireless powerless transfer conducted between the base station 195 andthe Bionode 170 involves conveying low frequency magnetic fields to theBionode 170 via magnetic fields oscillating at low frequencies (e.g.,960 kilocycles-1,060 kilocycles) to interact less with human tissue thancompared to electromagnetic fields oscillating at higher frequencies.

In some cases, the power transfer aspects may be accomplished accordingto the magnetic resonance coupling techniques described in related U.S.patent application Ser. No. 14/728,976 entitled “MAGNETIC RESONANCECOUPLING”, filed Jun. 2, 2015, which is incorporated herein by referencein its entirety. Moreover, in another embodiment, wireless powering canbe accomplished using near-field inductive coupling techniques. Forinstance, in some cases, the Bionode 170 is implanted proximate to theskin's surface of the patient 190, thus allowing for short-rangecoupling in a low-powered magnetic field generated between thenon-implanted base station 195 and the implanted Bionode 170. Variousother mechanisms employable for wireless power transfer may be utilized,as deemed necessary and/or appropriate.

In some cases, the non-implanted base station 195 supplies atime-varying magnetic field with time-dependent behavior and magnitudedesigned to elicit the desired stimulation current waveform in theBionode 170. The design of the optimal current waveform at the output ofa current generator in the base station 195 to produce the desiredstimulation waveform in the implanted system. Generation of currentwaveforms at the output of the base station's generator can involveproducing waveforms that are identical in shape and time-dependence tothe waveform intended to be delivered to the biological site, in orderto obtain the desired ranges of implant current stimulation waveformcharacteristics. In some instances, the system 100 is designed todeliver a biphasic rectangular pulse train stimulation waveform to thedesired biological site with waveform characteristics includingfrequencies from 1 Hz to 150 Hz, pulse widths from 50 μSec to 1000 μSec,and pulse magnitudes of 0.25 mA to 12 mA. Moreover, the waveformcharacteristics supported by the system 100 can be generated to surpassthe ranges of typical VNS waveform characteristics to provide maximumvalues in the ranges approved by the United States Food and DrugAdministration, employing frequencies between 10 Hz to 60 Hz, pulsewidths from 100 μSec to 500 μSec, and current magnitudes of 0.25 mA to 7mA.

In another embodiment, wireless power transfer capabilities are realizedthrough magnetic resonance coupling of the power management board 101 ofthe Bionode 170 with a cavity resonator (e.g., a cage that acts as anantenna and that also houses an animal into which the Bionode 170 hasbeen implanted). In this case, the implanted Bionode 170 is wirelesslypowered using a resonator based wireless power transfer system, in whichthe cavity resonator delivers power to the Bionode 170 inside of achamber. Accordingly, the microelectronics of the power management board101 is configured to provide power to the Bionode 170 transferred fromenergy of a magnetic field that is generated by the cavity resonatorwhile the implantable device is appropriately oriented inside of thechamber. The WPT system, including the cavity resonator, can bestrategically designed to: 1) maximize power transfer efficiency (PTE)through optimal impedance matching, 2) minimize resonator orientationmismatch sensitivity with the biaxial resonators on the power module,and 3) allow patient housing, namely rodents such as mice and rats forexperimental purposes. Energy is wirelessly delivered to the implanteddevice by coupling magnetic fields generated within a metallicrectangular cavity (e.g., TM₁₁₀ resonant mode; L×W×H, 60.96×60.96×30cm3) to the power management board 101 of the implant. The cavityresonator can be constructed from any suitable material that can thenproduce a magnetic field, such as various metals including aluminum,copper, and the like.

FIG. 1B is a block diagram illustrating an example of a wirelessplatform system 100 for implementing wireless recording and stimulatingof bioelectric events, in accordance with the disclosed techniques. FIG.1B illustrates the main sub-elements of the wireless Bionode 170, whichincludes the power management board 101 and the main board 120. In somecases, the power management board 101 can be stacked on top of the mainboard 120 to construct the implantable Bionode (as shown in FIG. 2C).Also shown in FIG. 1B are sub-elements of the base station 140.

The power management board 101 is illustrated as having variouscomponents configured to implement the power related aspects of theBionode 170, including but not limited to: two receive coils 104utilized in the wireless power transfer; two j-inverters 106; a fullwave rectifier 107; and a voltage regulation 108 element. The powermanagement board 101 can be configured to provide two different supplyvoltages 109 and 110 to run the microelectronics in the main board 120.The different supply voltages 109 and 110 may be of different levels,for example, 1.8 volts for supply voltage 109 to supply (1) analogfront-end circuitry 121 and 122 for two recording channels, (2) theprocessor unit 135, and (3) a bi-directional telemetry component 129 tocommunicate data to and from the non-implantable base station assembly140, and 11.2 volts for supply voltage 110 to supply the stimulationgeneration circuitry 130. According to the embodiments, the Bionode 170is enabled with two-way telemetry involving transceiver 129 with theexternal base station 140, also having a transceiver 146. The basestation 140 can use a single board computer (SBC) 142 that can be usedto relay the data via a wireless network connection, such as Wi-Fi, to acomputer, such as computer 160 shown in FIG. 1B having data acquisitioncontroller software. For example, the SBC 142 may be implemented usingRaspberry Pi along with custom circuitry. For example, the base station140 can use Raspberry Pi along with a custom-made PCB that has theamplifiers and waveform generators for powering along with the radio DSPcomponents for telemetry.

FIG. 1B illustrates the computer in communication with the base station140, as a laptop 160. Generally, the computer 160 may be used by a userto program operation of the base station 140 and Bionode 170, andreceive data regarding the operation of those components. Although shownas a laptop 160, various other personal computing device can beutilized, such as a desktop computer, tablet, or smartphone. The laptop160 includes a processor, which can be one or more hardware processors,which can each include multiple processor cores. Also, the laptop 160can include a memory, such as volatile and non-volatile memory, forexample Random Access Memory (RAM) and Flash RAM.

Furthermore, laptop 160 (or any computing device communicatively coupledwith the Bionode 170 and the base station 140) is configured to executesoftware related to the capabilities of the Bionode 170, such as therecording and stimulating of bioelectric events. In someimplementations, data acquisition controller software can be installedon the laptop 160. As an example, the data acquisition controllersoftware is written in a high level programming language, such asPython3. Moreover, the software can be used to display data in a uservisible format on the display device of the computer, for instance asreal-time data plots. This software running on laptop 160 can also serveas a user interface (UI) for controlling functional parameters of thesystem, such as sampling rate, ADC resolution, and stimulus waveformsettings, features particularly useful in research settings involving,for example, an animal subject.

Additionally, users of the system 100 can communicate with the Bionodesystem 170 through the base station 140 using a software applicationcalled Bionode DataView. In some instances, the system software can bewritten for portability to various computing platforms, such asMacintosh, Windows, and Linux operating systems, which allows theapplication to be built for and deployed to a wide range of computingdevices. To further increase the ease of deployment, the base station140 creates its own Wi-Fi connection, allowing any device with Wi-Ficapabilities to communicate with the base station 140 without the needof additional hardware drivers. The Bionode application can also providea graphical user interface that displays all acquired data and currentBionode 170 and base station 140 settings in real time. The userinterface allows the user to set Bionode stimulation parameters as wellas initiate and terminate stimulation sessions. Moreover, data packetscan be recorded through the Bionode application into a desired fileformat, such as a binary data file. Subsequently, these raw binary filescan be either analyzed directly, or exported as .wav files, which areeasily importable, by multiple data analysis tools (i.e. MATLAB, Spike2, etc.)

The power management board 101 can be employed to realize wireless powertransfer (WPT) with a cavity resonator (as shown in FIG. 1B, which canbe a cage that houses an animal and also acts as an antenna towirelessly power the Bionode) or with a wearable base station device(shown in FIG. 1A). The pairing of the cavity resonator and each coil104 in the power management board 101 can be operatively described asfunctioning in the manner of a 2-port band-pass filter. For instance,power transfer efficiency (PTE) is optimized by impedance matching andmaximizing the unloaded Q, Q0, and the powering frequency.

The power management board 101 can act as a power supply by coupling RFenergy and rectifying the induced current to DC. Orientation mismatch ofthe transmitter can introduce challenges in some cases, such as in thecase of freely behaving experiments. While use of the resonant cavitycan yield improved performance in comparison to some conventional WPTsystems, it is not immune to non-optimal performance. For better WPTrobustness, with respect to device orientation, two perpendicular coppercoils with separate impedance matching J-inverter 105 topologies and asingle full-wave rectifier 107 can be implemented for biaxial RF-to-DCconversion, as shown in FIG. 1B. The output of the rectifier 107 isshown as being fed to a voltage regulation element 108, that can be alow-dropout (LDO) linear regulator, to produce a voltage supply (e.g.,1.8 V) to the main board 120 components, such as the analog front ends(AFEs) 121, 122, thermal sensor 123, the MCU 135, and stimulationcircuitry 130.

Also, the power management board 101 can provide a voltage supply,(e.g., 11.2 V) to a current controlled stimulator (CCS), illustrated inFIG. 1B as the stimulation (“stim”) circuitry 130. An unregulated supplyvoltage can be buffered with a 47 μF storage capacitor and surgeprotected by a 5.6 V Zener diode, for example. As an example, the powermanagement board 101 may have a 7×12 mm footprint and be fabricated witha 2 layer FR-4 PCB. In an implementation, the power management board 101and the main board 120 connect at the two regulated outputs and deviceground.

To accommodate the powering requirements of the Bionode system 170, thepower management board 101 can be designed to provide a specified amountof power, for example, 16 milliwatts of average power. In some cases,the power management board 101 can be configured with the ability toproduce up to 60 milliwatts of peak power, for example. This power istransferred to the Bionode 170 through voltage rails (109 and 110) thatare used by the Bionode's acquisition circuitry 121, 122, and 123,microcontroller 135, and stimulation circuitry 130.

The power management board 101 can use two secondary coils orientedorthogonally to each other (or a single coil bent 90 degrees) to collectenergy from a circulating magnetic field inside of the chamber housingof the resonator. The orthogonal orientation of these two coils allowsthe power management module 101 to more consistently collect energywhile the implant is in varying orientations within the WPT chamber. Thepower transferred to each coil can be maximized via animpedance-matching admittance inverter network on the power managementboard 101 tuned to the resonant frequency of the chamber (e.g.,approximately 340 MHz). The power management board 101 can includecircuitry implementing an impedance matching network. As an example, theimpedance matching network includes two capacitors, which initially havevalues predicted by bandpass filtering theory. These capacitor valuesare further tuned based off of measured resonant responses of thesystem. The circuitry utilized for implementing the impedance matchingaspects of the power management board 101 are discussed in detail inreference to FIG. 9 below.

The control module, implemented as the main board 120, can be generallydescribed as the brain of the Bionode. FIG. 1B illustrates the mainboard 120 as including, but not limited to: analog front ends (AFEs) foreach of the two channels, namely CH1 AFE 121, and CH2 AFE 122; thermalsensors 123; microcontroller unit (MCU) 135; stimulation circuitry 130;and impedance test circuitry 131. Furthermore, the MCU 135 is shown asincluding internal elements, including: an analog-to-digital (ADC) input1 124; ADC input 2 125; inter-integrated circuit i²C port 126; serialperipheral interface (SPI) port 127; general purpose input/output (GPIO)128; and transceiver 129.

The main board 120 is configured to implement multiple operationalfunctions of the Bionode 170, including but not limited to: biopotentialacquisition, biomodulation, electrode impedance monitoring, thermalmonitoring, and bidirectional telemetry. The main board 120 has thecircuitry for the recording and stimulating channels, as well as amicrocontroller 135, radio, and antenna for data transmission andreception (transceiver 129). The main board 120 is shown to produce anelectrical output, stimulation output signal 134, which can be used tostimulate a nerve, for instance, at the implanted biological site of thepatient, in the case of biomodulation.

A system-on-chip (SoC), (e.g., SoC, NordicnrF51822) may be utilized torun and coordinate the multiple protocols of the Bionode. In animplementation, the SoC may contain a 32-bit ARM Cortex-M0: a MCU 135with 256 kB of flash memory, which allows for rapid changes to thedevice's functional protocol through reprogrammable firmware.

The main board 120, in some cases, may be a six-layer FR-4(glass-reinforced epoxy) printed circuit board (PCB) (39.37 milthickness) and fabricated for example by Advanced Circuits (Aurora,Colo.). The footprint of the main board 120 can be deigned at 7 mm×12mm. Given close proximity of the mixed signal microelectronics, a designconsideration for layout is to physically isolate the analog, digital,and radio frequency (RF) blocks of the Bionode.

Biopotential acquisition can require specific electrical features, suchas high differential input impedance, low noise, high common-moderejection ratio (CMRR), and sufficient gain and bandwidth. Accordingly,in an effort to achieve desirable features, the main board 120 isconfigured with two parallel AFEs, shown as CH1 AFE 121, and CH2 AFE122. Each AFE can have a two-stage gain topology (shown in FIG. 3A).Each of the AFEs 121, 122 are shown as receiving differential inputs132, 133 respectively. The inputs —differential inputs 132, 133—can besignals transmitted from a differential pair of electrodes that can beused for ECG recording, for example.

In some cases, the gain and bandwidth of the AFEs 121, 122 can bereconfigured individually through passive component selection but alsomay be limited by the gain bandwidth product of the second stage (200kHz). The total gain for both channels is set to 60 dB, in anembodiment. The first stage (20 dB gain) of an AFE 121, 122 can use anamplifier (e.g., INA333 instrumentation amplifier, Texas Instruments)due to its characteristics, such as 100 GΩ differential input impedanceand 50 μA power consumption. The second stage (40 dB gain) of the AFEs121, 122 can be AC coupled with an inverting bandpass filter topology.The output of the second stage is then routed to an ADC, for instance a10-bit analog-to-digital (ADC) embedded in the SoC. Also, low pass inputfilters can be used within the AFEs 121, 122 to decrease RF interferencein WPT. Implementation of front-ends can impact matching anddifferential input impedance, in some instances.

The Bionode system's AFEs 121, 122 can have a measured CMRR of >80 dBfrom DC to 60 Hz and a measured input-referred noise of 2.3 μV. Forpurposes of analyzing performance characteristics of the recordingchannel for the Bionode 170, input-referred noise, gain, and bandwidthmeasurements were performed using an Agilent 35670A dynamic signalanalyzer.

According to some embodiments, the Bionode 170 is supported by variousexternal systems. In this case, the wireless platform system 100includes a Wireless Powering Transfer (WPT) chamber 150. The WPT chamber150 can provide both power to the implanted Bionode and a living spacefor the implanted subject rodent. Data wirelessly transmitted to and/orfrom the Bionode 170 can pass through the base station 140 that providesa communication interface between the Bionode 170 and a computingdevice, illustrated as a laptop 160 in FIG. 1. The communicationinterface to the laptop 160 can be implemented via a wireless link usingvarious wireless networking technologies, for example Wi-Fi. A customdesigned cross-platform application for the system 100 can be configuredto provide a graphical user interface, which can be displayed on thelaptop 160 for example, and used to allow users to view and save datatransmitted by the Bionode 170 as well as specify various settings(i.e., stimulation waveform parameters) on the Bionode 170. Expectedvalues versus measured results for one implementation can be shown forthe following parameters:

Value Category Specification A/E [Expected] Measured Stimulation Numberof channels and A 1 1 single-ended and type (single-ended/ Differentialblocking differential) Pulse frequency range A 20 kHz 0.01 to 20kHz(Pulse frequency is measured from positive stim (rising)edge tonegative stim (falling) edge) Pulse shape (rectangular, A rectangularrectangular fixed pattern, arbitrary) Amplitude range of pulse A 0 to 1mA 0 to 1.06 mA control (for electrical stim/block) Compliance atmaximal E 0.01 mA 0.015 mA amplitude (for electrical stim/block) Rangeover which duty A 0% to 100% 0-100% cycle can be configured Wirelessstimulus A 25 kSps and Not implemented in BN4.1 monitoring rate and 8bit depth resolution (if available) Offset voltage build-up E 0 mV 1.2V@1000 uA Pulse Amplitude, after continuous 50% 50 us Pulse Width, 100us Pulse duty cycle stim at 10 kHz Period over a low-leakage capacitor(e.g. ceramic, testing setup info available on request) Nerve Number ofchannels and A 2 2 Differential Recording type (single-ended/Differential differential) Total input referred noise E 1.77 μV 3.1 μVRMS @ 1 kHz at relevant frequency RMS @ band and gain 1 kHz Range ofamplifier gains A 60 dB in 1 59.9 dB steps Input range A 1.2 mV Analogchannel A 10 Hz to 5 kHz N/A bandwidth (HPF to LPF) (selectable duringassembly, not after) ADC dynamic range and A 10 bits Not present innRF51822 datasheet effective resolution Simultaneous operation E yes yeswith stim/block Power & Battery type (primary or A None Lithium Ion(LiR1220) 12 mAh telemetry rechargeable) and capacity (if any) Powertransfer frequency A 335 to 340 MHz 335 to 345 MHz (if rechargeable)(enclosed cavity volume) Average power transfer A N/A N/A rate @ 5 cm inmoving animals (if rechargeable) Average power budget A 19.28 mW 18.52mW(1 mA, 11 k, 50%) for overall system at worst-case stimulation/ blockAverage power budget A 7.28 mW 5.288 mW for overall system whilerecording Maximal implant depth, E 10 cm, 2 number of data (and coilspower) coils in the implant Data telemetry protocol A Custom Custom, 2Mbps and rate (up- and type, 250 kbps downstream) Base-station: Txpower, A TX: 4 dBm, −85 dBm per nRF51822 datasheet Rx sensitivity (Atthe RX: −85 dBm input/output of the microcontroller) Implant: Tx power,Rx A TX: 4 dBm, −85 dBm per nRF51822 datasheet sensitivity (At the RX:−85 dBm input/output of the microcontroller) Implant Weight of the E 1.5Gram 9 Gram(10 Gram with bat) packaging implantable device Size of theimplantable E ~1 cm³ (.5 r × 6.18 cm³(.75 r × 3.51(4 cm with device(s),L × W × H 1.41) bat)) (cylindrical) Insulation material for A Si wires,Silicone, Epoxy and Glass wires and implant (e.g. epoxy Teflon, epoxy,silicone) implant Number of wires in the A 7 2-7, depending onapplication cable to electrodes (including ground) Cable connector and ANA NA number of leads for recording, stimulation, and sensors

Two major modalities of biomodulation are electrical and optical. Safetyparameters for electrical stimulation have been extensivelycharacterized, and protocols should be charge balanced with biphasicwaveforms. Other stimulation parameters such as frequency, pulse width,and pulse pattern distribution are lesser studied and are of interestfor biological efficacy and decreased power consumption. Acurrent-controlled stimulator (that may be utilized in a Bionode) mayuse an op-amp constant current sink that draws charge from a 11.2 Vsupply (provided at voltage supply 110, shown in FIG. 1B, for example).Charge balanced biphasic stimulation is enabled by a dual-poledual-throw (DPDT) switch at the electrode inputs. An on-board 12-bitdigital-to-analog converter (DAC) provides the reference voltage. Allstimulation parameters are controlled by protocols in the MCU 135. Theperformance of the stimulator is evaluated by connecting the stimulatoroutputs to a known load impedance (10 kΩ) and sweeping the stimulator'sfunctional parameters (e.g. pulse width, current amplitude, and pulserepeat time/duty cycle). A sample of the biphasic stimulator output,illustrated as “stim out” 134, for a range of stimulus current amplitudesettings at a 50% duty cycle is given in FIG. 4. The measured chargebalance is 6 nC at a pulse width of 1 ms. The current controlledstimulator (CCS) can deliver up to 1.12 mA across a 10 kΩ load owing toits 11.2 V headroom.

Optical stimulation for use in optogenetic experiments can be configuredby replacing the electrodes with an optical module for deep brainstimulation and disabling the biphasic stimulation. Of experimentalinterest, blue light emitting diodes (LEDs) typically have the highestforward voltage at 3.0-3.3 V. The 11.2 V headroom is more thansufficient to drive the LED.

FIG. 2A and FIG. 2B show a top and bottom view, respectively, of anexample of a Bionode control module or main board 200, 210 (that is, anexample physical configuration of the main board 120 shown in FIGS. 1Aand 1B). As shown, the main board 200, 210 is a printed circuit board(PCB) assembly. In FIGS. 2A-2B, the main board 200, 210 is illustratedas fully populated with the microelectronics operating in concert toimplement the various functions associated with the Bionode, namely themain board (shown in FIG. 1). The main board 200, 210 can be implementedusing integrated circuit (IC) chips and passive components to achievevarious aspects of the Bionode, such as the two differential recordingchannels, one current controller, biphasic stimulator, thermal sensing,electrode impedance measurement, and two-way telemetry. It should beappreciated from FIGS. 2A-2B that the Bionode's microelectronics fitwithin the main board 200, 210 having a characteristically smallcircuitry area, and similarly a small footprint. In some cases, theboard 200, 210 can have a footprint measuring 7 mm×12 mm. Amicrocontroller can be included in the microelectronics of the mainboard 200, 210. In an implementation, the main board 200, 210 hasinstalled thereon a microcontroller implemented as an ApplicationSpecific Integrated Circuit (ASIC), which is an integrated circuit (IC)programmed for a specific use. In some implementations, the ASIC can bepowered wirelessly according to the wireless powering aspects describedherein. For instance, the ASIC can be powered wirelessly at 13.56 MHzusing a powering wand and a loop antenna on the circuit board 200, 210.Additionally, the main board 200,210 includes the electronics needed toconvert an electromagnetic wave to a DC voltage, for example 1.8 V, topower the ASIC.

In an embodiment, maximum dimensions of the microelectronic platformshown in FIGS. 2A-2B, once populated, may be 12 mm (length)×7.5mm(width)×2.5 mm (height). The circuit illustrated as main board 200,210can be designed for optimal impedance matching of the receive coils,power rectification, and power management module placed on a twin boardand stacked. Once integrated, main board 200, 210 plus the receive coilsystem can increase the total device form factor to 15 mm (length)×7.5mm (width)×5 mm (height) for a total device volume of −0.6 cc. Thestimulator can be current controlled with a 12V headroom, for instance.In accordance with the microelectronic implemented in main board200,210, the Bionode may be equipped with two differential recordingchannels, one stimulating channel, thermal sensing, and electrodeimpedance measurement. In an embodiment, the device logic may useoff-shelf electrical components, for example an ARM CORTEX M0microcontroller.

FIG. 2C shows an example of a wireless implantable device, or Bionodesuch as 170 shown in FIGS. 1A and 1B, for implementing the disclosedtechniques. As shown in FIG. 2C, a power management board is stacked ontop of a main board to create a fully assembled Bionode 223. FIG. 2Cillustrates the Bionode 223 including a header 222 with crimp pins. Insome embodiments, the header 222 is optionally used to remove andreplace electrode leads 221, 241, 341. The Bionode 223 can be covered bya shell 220, which is depicted as being removed from the Bionode 223. InFIG. 2D, the Bionode 223 is illustrated as being encapsulated inside ofa shell 240. In some cases, the shell 240 is a molded medical epoxyshell.

FIG. 2C also illustrates a loop antenna 224. The loop antenna 224 can beconnected to the board of the Bionode 223. The loop antenna 224 can beused for wireless transmission of data to and/or from the Bionode 223.As an example, the data is transmitted to the loop antenna 224 at 3 GHz.

FIG. 3A is a diagram of an example for circuitry implementing an analogfront-end (AFE) for a recording channel of the Bionode, such as AFEs 121and 122 of FIG. 1B. The circuitry 300 can be configured in a manner thatimplements various advantageous electrical design characteristics forthe sensing aspects of the Bionode, such as a high differential inputimpedance, low noise, a high common mode rejection ratio (CMMRR), andsufficient gain and bandwidth. As a general description of the circuitry300, the front-end filter 305 allows for passive bandpass filteringprior to amplification. The first stage 310 in capable of operating asan amplification stage, which differentially amplifies the signal. Theamplification within the first stage 310 can be achieved using aprecision instrumentation amplifier 311 with minimal gain, for example.The second stage 315 can also operate as an amplification stage. Thesecond stage 315 can have a substantially higher gain in comparison tothe first stage 310, and is configured to implement active bandpassfiltering.

In some implementations, various electrical parameters can be adjusted,for example the gain and bandwidth can be set for each input channel inorder to properly condition the various signals that may be sensed bythe circuitry 300 (i.e., electrocardiogram (ECG), electrocorticogram(ECoG), electromyogram (EMG), local field potential (LFP), compoundnerve action potential (CNAP), thermocouple sensor inputs, or pressuresensor inputs). While the circuitry 300 can filter out noise generatedby the some sources (i.e., nearby-radiated signals, motion artifacts,and other biological signals), it can be configured to filter out highfrequency noise, for example noise that is injected into the signal pathfrom the wireless power transfer (WPT).

According to the embodiment of FIG. 3A, the Bionode has two paralleldual-ended AFEs, for instance one for each input channel. Each of theAFEs can be designed using the circuitry 300, which include passivefront-end filtering 305 coupled with a first stage 310 and a secondstage 315. The stages 310,315 are configured for gain amplification. Thefirst stage 310 implements differential amplification and the secondstage 315 can be a high-gain stage that also provides band-passfiltering. These parallel AFEs are dual-ended with rails, for example,+0.9V rails to allow the AFE to have a zero DC bias voltage. This can beutilized in the instances where the stimulation circuit requires thatthe negative stimulation electrode is connected to the Bionode's ground.If the AFE had a non-zero DC bias voltage, a static potential couldexist between the recording electrodes 301 and the negative stimulationelectrodes; which can potentially cause tissue damage, electrodeerosion, and unintended stimulation performance.

Further, in alternative embodiments of the circuitry 300, the passivefront-end filtering 305 can be configured to provide the option toinclude the passive high pass filter, low pass filter, or bandpassfilter before the first stage differential amplifier. While adding thesefilters can reduce the CMRR and the differential input impedance of theAFE, it can be advantageous for the design to implement these filters incertain conditions. As an example, in the instance of directly sensingbio-signals with differential leads (i.e., ECG, ECoG, or EMG), adrifting DC offset voltage may be observed which can cause the inputs tothe instrumentation amplifier 311 in the first stage 310 to drift out ofthe DC voltage input range of the instrumentation amplifier 311. Toaddress this problem when measuring signals, such as biopotentialsignals, a passive high-pass filter can be populated in the front-endfiltering stage of the AFE. A similar issue has also been observedrelated to high-frequency conditions, for example when providing powerto the Bionode using a high frequency inductive link. High frequencyradio frequency (RF) noise can couple onto the leads and traces of theBionode when inductively powering. To compensate for noise, thecircuitry 300 can be configured to remove the noise by populating apassive low-pass filter in the front-end filtering 305 stage of the AFE.If operating the Bionode under conditions where both of theaforementioned problems arise (i.e., wirelessly powering a Bionode whilemeasuring ECG), a passive band-pass filter is populated in the front-endfiltering 305 section of the AFE circuitry 300. In the case of operatingvoid of the aforementioned problematic conditions, the front-endfiltering 305 section can be bypassed by implementing a specificcircuitry. As an example, the bypass is implemented by populating the R1306 and C1 307 pads with zero ohm resistors and not populating the R2308 and C2 309 pads; providing input channels with higher differentialinput impedance and CMRR.

Examples of performance characteristics for one AFE circuitry 300 of theBionode can be shown for the following parameters:

Value No front-end Low-pass Bandpass Parameter filters front-end filterfront-end filter Gain 60 dB 60 dB 59.9 dB High-pass cut off 10.47 Hz 4.9Hz 6.0 Hz Low-pass cut off 1.410 kHz 1.48 kHz 1.46 kHz CMRR 100 dB 43 dB72 dB Input impedance 100 GΩ 3.61 MΩ 2.03 MΩ Input-referred noise 51.85nV/√Hz 101 nV/√Hz 97.3 nV/√Hz

The first stage 310 can include a ground referenced instrumentationamplifier 311 that differentially amplifies its input signal. Anamplifier 311 can be chosen as a design choice based on variouscomponent characteristics, such as its high input impedance (i.e., 100GΩ), low power consumption (i.e., 50 μA), and low operating voltage(i.e., 1.8 V). The value of the RG 312 resistor can determine the gainof the instrumentation amplifier 311. For example, the gain foramplifier 311 can be set to 20 dB (RG=11 kΩ). This is comparativelysmaller than the gain of the second stage 315, so as to reduce noise.

The second stage 315 is shown as implementing an inverting band-passfilter topology, using an operational amplifier 316. The amplifier 316can be chosen because of various component characteristics, for instancesufficient gain bandwidth (1 MHz), low noise (25 nV/sqrt(Hz)), andrail-to-rail output. In some cases, an amplifier 316 has the addedbenefit of being available in a compact dual-package form factor whichallows one IC to be used to implement both AFEs, thereby reducingcircuit area. The gain and bandwidth of the second stage 315 can bereconfigured individually by adjusted by appropriate component valuesfor RS 317, CS 318, RP 318, and CP 319. The gain for the second stage315 can be set to between 20 and 50 dB, as an example.

The outputs 320 of the circuitry 300 for each of the AFEs are routeddirectly into two of the microcontroller's ADC inputs. A microcontrollerfor the Bionode system can be powered off of the same ±0.9V rails thatpower the AFEs, which can potentially remove the necessity for theoutputs of the second stages 3 15 to be transformed into single-endedsignals. This allows the outputs to be routed directly into the ADCinputs of the microcontroller. In some implementations, themicrocontroller's ADC can be configured to acquire samples at either8-bit or 10-bit resolution with a total sample rate of up to 25 kHz,which is selectable by the user via the bidirectional communicationinterface.

FIG. 3B shows an example of circuitry 340 for implementing constantcurrent stimulation aspects of the wireless implantable device. In someimplementations, a current stimulation waveform that is constant, orotherwise substantially constant, can be applied to the Bionode. As ageneral description of the circuitry 340, a constant current stimulationis generated via a current source 342. The output of the current source342 can be set by the microcontroller of the Bionode via thedigital-to-analog converter (DAC) 341. A normally grounded controlswitch 343 can be used to potentially prevent unintended stimulationfrom occurring, for example during a power on sequence. To enablebi-phasic stimulation, a positive stimulation electrode 344 can swingaround the negative electrode 345 which shown as being tied directly tothe Bionode's ground 346.

As discussed above, the current stimulation can be constructed using acurrent source 342, which is driven by the digital-to-analog converter(DAC) 341. FIG. 3B illustrates the current source 342 as a Howardcurrent source (HCS) that converts a control voltage provided by the DAC341 into a current waveform. The DAC 341 topology is shown, but othertopologies like current mirroring or electrode polarity switching (wherethe positive and negative electrodes are physically switched) can beimplemented. The configuration in FIG. 3B may realize advantagesassociated with a DAC generating reliable symmetric bipolar currentpulses. Difficulties relating to achieving symmetric pulses can beexperienced in cases where current mirroring topologies are used, forexample due to part tolerances. Also, electrode polarity switching cansometimes create asymmetric responses in stimulated nerves, as anexample due to the physical change in anodic and cathodic electrodeplacement.

In the current source 342 of circuitry 340, the output current I isrelated to the control voltage V_(CTRL) by the following equation:

$\begin{matrix}{I\; = \; \frac{V_{CTRL}}{R_{S}}} & (1)\end{matrix}$

In some implementations, R_(s) 347 is a current limiting resistorconfigured such that the particular design requirements, such asspecified stimulation current amplitude and precision, can be met. Forexample, a Bionode can be designed to provide a maximum stimulationcurrent of 1 mA through a 10 kΩ electrode impedance. In some cases,because the output voltage range for the DAC which provides V_(CTRL) is−0.9V to 0.9V, R_S was set to 800Ω, it allows for the current source 342to provide current outputs ranging from −1.125 mA to 1.125 mA. In orderto drive this current across a 10 kΩ electrode impedance, for example,the current source 342 is powered by a ±10.5 V supply 348 which canallow a maximum voltage of 10.5V to appear at the output terminal.

According to an embodiment, stimulation waveforms are created by a12-bit DAC 341 which is controlled by the Bionode's on-boardmicrocontroller via a serial peripheral interface (SPI). Thesestimulation waveforms are generally biphasic rectangular pulses, whichmay be defined by a user in terms of amplitude, pulse width (TPW), andpulse repeat time (TPRT).

As an example, a user may define these parameters using softwaresupported by the platform, such as a Bionode application, whichsubsequently instructs the Bionode to set interrupt registers in itson-board microcontroller. These interrupt registers can define thestimulation waveform by specifying when DAC 341 output voltage updatesmust occur. To further increase the accuracy of the DAC 341 output,calibration registers may also be defined by the user which are used bythe microcontroller to automatically compensate for static DC offsetvoltages that may be present on the output of the DAC 341. There can bea range of these DC offset voltages, and calibration values tocompensate for these offsets can be obtained experimentally during thefabrication of each Bionode.

Additionally, the circuitry 340 illustrates a single pull double throw(SPDT) switch 343 is placed between the DAC 341 output and the currentsource 342. The switch 343 can be employed to avoid any start-upglitches on the output of the DAC 341, which can potentially beexperience when the DAC 341 is first powered on. If not avoided, thisglitch may cause the stimulator circuit 340 to output an unwantedstimulus pulse every time the Bionode is powered on.

The switch 343 is controlled by the on-board microcontroller and has apull-down resistor 349 attached to the control line which can helpensure that the switch 343 is in position zero even when themicrocontroller is powering on and not yet driving its voltage level.When at position zero, the switch 343 connects ground to the V_(CTRL)line of the current source 341, causing the stimulator to not output anycurrent. When at position one, the switch 343 connects the output of theDAC 341 to V_(CTRL), allowing the DAC 341 to control the current outputof the stimulator circuit 340. For safety reasons, it may be desirableto set the switch 343 to position one when the user has specified thatstimulation should occur.

A list of the key performance specifications for the stimulator areshown for the following parameters:

Parameter Value Units Voltage headroom 10.5 V Current amplitude¹0.005-1.050 mA Current amplitude  4.4 μA resolution Pulse width (T_(PW))  50-8.36e6 μs Pulse width resolution  1 μs Pulse rate  1e−5-20 kHzCharge balance error² <0.5 %

FIG. 4 is an example graph 400 displaying current-controlled, biphasicoutput measured from the stimulator outputs of a Bionode. In thisexample, the stimulator output is measured on a benchtop using a 10 kΩload across the stimulator outputs. The graph 400 displays the outputsignal as a relationship between time (ms), along the X-axis, versuscurrent (A) along the Y-axis. Pulse width, current amplitude, and dutycycle can be selectable parameters in real-time through reversetelemetry from the base station to the Bionode. A pulse width of 1 msand a 50% duty cycle are used here to illustrate the current output fora range of amplitude settings.

FIG. 5 is an example of a graph 500 displaying root-mean-square (RMS)voltage measured employing the electrode impedance measurementcapabilities of the Bionode. For instance, the measured RMS voltagegraphically represented in graph 500 can be recorded across a series ofknown load impedances, while running electrode impedance measurementcircuitry. The graph 500 displays the RMS voltage signal as arelationship between impedance (kΩ), along the X-axis, versus theV_(RMS) (V) along the Y-axis. A prediction curve can be calculated tofit to this data, and exhibit an R2 value of 0.994. Further, theprediction curve can be used to approximate the electrode impedance at afixed frequency.

FIG. 6 is an example of a graph 600 displaying plotted points oftemperature sensor measurements and curve of thermocouple change. Thegraph 600, as an example, is a graphical representation of a comparisonof temperature IC and thermocouple tracking change in environmenttemperature. The graph 600 displays the relationship between time (min),along the X-axis and temperature (° C.) of the thermocouple and thetemperature sensor measurements, along the Y-axis.

FIG. 7 shows an example of a format for a data packet structure, used inimplementing a wireless communication protocol. For example, a datapacket 700 having the format displayed in FIG. 7 can be transmitted,during wireless communication, from the Bionode to be received by acomputer device running software for the Bionode platform. Asillustrated, the data packet 700 is formatted in accordance with theBionode's wireless communication protocol to include various fields thatcan be divided into three main segments: a header 710, a payload 720,and a CRC 709. The header 710 section of the data packet 700, includesone or more fields: Synchronization (SYN) 701; Packet ID (PID) 702;transmission ID (TXID) 703; receiver ID (RXID) 704; and TYPE 705. In thepayload 720 section, the format has one or more fields including:recorded data 706; stim status 707; and time stamp 708.

Further, each the fields of the packet's format include informationusable to support wireless communication aspects of the system. SYN 701:synchronization bytes equal to 0xA55A indicating the start of a packet.PID 702: packet ID generated by a running counter that indicates thenumber of packets sent since power on. TXID 703: indicates packet origin(PC, Base Station, or Bionode). RXID 704: indicates intended recipient(PC, base station, or Bionode). TYPE 705: packet type which categorizesthe content of the payload section of the packet. Recorded Data 706:contains either 40 8-bit data samples or 32 10-bit data samples. Dataresolution is defined by the preceding TYPE byte. Stim status 707: eachbit indicates whether the stimulator was stimulating or not during theacquisition of each corresponding data sample in the recorded datasegment of the payload. Time Stamp 708: a 4-byte time stamp added by thebase station which can be used in tandem with the PID by the PC todetermine the sampling rate of the data as well as the duration of anylost data. Lastly, CRC 709: a 16-bit cyclic redundancy check used todetermine the validity of each packet.

The packets 700 that are transmitted to and from the personal computer,base station, and the Bionode (shown in FIG. 1) can contain the sameheader 710 and CRC 709 sections. In some embodiments, the payload 720section varies depending on the type of data being transmitted in thepacket 700. The header 710 section is used by the base station toproperly route one or more packets 700 it receives, and the contents ofthe header 710 can also be analyzed to determine if a packet 700 hasbeen routed incorrectly. The leading SYN bytes consist of the bytes0xA55A. These bytes allow the beginning of a data packet 700 to be foundin cases where partial packets may be missing from the data stream. Thisis likely to occur during a serial transmission that occurs between thebase station's microcontroller and the base station's on-board RaspberryPi (shown in FIG. 1). The next bytes in the data packet 700 contain anincrementing packet ID number. The packet ID number is set andincremented by the device that is transmitting, or otherwise sending,the data packet (i.e., personal computer, the base station, or theBionode) and is used to determine if packets have been missed by thereceiver. The next two bytes in the packet 700 contain the ID numbers ofthe transmitting device that sent the packet (0=PC, 1=Base Station,2=Bionode, 3=Invalid), and the device that is the intended receiver.These bytes tell the base station where to route all incoming packetsand inform the receiver of where the incoming data packet came from. Thefinal byte of the header 710 contains the type ID of the packet 700which indicates the type of data is contained in the payload 720. Thetypes of payload data and their associated type IDs are shown in thetable below:

Type ID Packet Type 0 8-bit data sampled by the Bionode 1 10-bit Datasampled by the Bionode 2 Lead impedance measurement 3 Thermistor readingfrom the Bionode 4 Bionode register configuration 5 Base stationregister configuration 6 Identification response 7 Identification ping 8Invalid packet 255 Shutdown Base Station Command

FIG. 8 shows a diagram depicting the communication paths between thecomponents of the wireless platform system, including the Bionode 820,the base station 810, and the personal computer 801. Bidirectionalcommunication during use of the system can greatly increase theflexibility and possible application use of an implantable device. Theability to transmit data potentially removes the burden of on-board datastorage from the implantable device, but it also allows the implantabledevice to communicate its current status and settings in real time;allowing for increased confidence in implant performance over time.Furthermore, the ability to receive data allows the implantable deviceto be configured, calibrated, and instructed before, during, and afterimplantation; increasing its adaptability to varying circumstances. Animplantable device that can both receive and transmit data has the addedbenefit of allowing an external user or system to reactively sendinstructions to the implantable device based off of recorded dataobtained by the implantable device; effectively creating a closed-loopsystem.

A potential challenge to implementing bidirectional communication in animplantable device is handling the increase power consumption introducedby radio communication circuitry. In many cases, including that of theBionode 820, the most power-hungry system on implantable device is thetransmit and/or receive radio. Power consumption on the Bionode 820 canbe greatly reduced while transmitting and receiving data by tightlycoordinating when data transmissions occur.

The microcontroller on the Bionode 820 is configured to communicate datatelemetry coming into and out of the device. The microcontroller for theBionode 820 can be selected to achieve desirable componentcharacteristics, such as low-power sleep states, small size, on-boardradio, and on-board analog to digital converter (ADC). For example, amicrocontroller can be utilized that only draws 2 μA of current when itis in sleep mode, and draws 20 mA of current when the radio isactivated, an interrupt-driven firmware design was developed in order tokeep the microcontroller in sleep mode with the radio deactivated asmuch as possible.

Bidirectional communication can be performed, as illustrated in FIG. 8,by enforcing a coordinated handshake protocol with a custom designedexternal base station 810 which facilitates all communication betweenthe Bionode 820 and any outside user. After the Bionode 820 acquires aspecific number of samples, for example 40 data samples, from its ADC,the microcontroller of Bionode 820 initiates a data-packet transmissionto the base station 810 using the on-board radio. Data packets can beconstructed, for instance using conventional packetization techniques,to include recoded data, and subsequently communicated via transmissionsignal 832 from the data packet constructor 821.

In some cases, the radio is a 2.4 GHz ISM band radio. This isillustrated as transmission signal 837 to ADC Data available interrupt825, for example. In some cases, a transmission signal 838 received bythe thermal sensor 826 can initiate data-packet transmission from theBionode 820. In most cases, the radio is activated during thistransmission which lasts approximately 1 millisecond.

However, after a successively transmitting multiple packets, forinstance the 100th data packet, Bionode 820 initiates a hand-shake withthe base station 810. The handshake can be performed between theBionode/base station handshake 817 unit of the base station 810 and thehandshake data handler 823 of the Bionode 820.

After transmitting a specified data packet, or a data packet otherwisedeemed as the end of communication (e.g., 100th data packet), theBionode 820 sets its radio to receive mode, and listens for a datapacket from the base station 810 for a time, typically not exceeding 10milliseconds. This gives the base station 810 an opportunity to send asingle data packet to the Bionode 820. The data packet can contain a45-byte long payload, which is used to set firmware registers in theBionode 820 microcontroller that store data acquisition, stimulation,and communication settings. The registers are shown in FIG. 8 as Bionoderegisters 822. Because the payload contains values for writeablefirmware Bionode registers 822, the Bionode can be fully configured andinstructed during this single data transmission.

In some cases, the handshake driven communication scheme allows theBionode 820 to transmit acquired data rapidly, while maintaining theability to receive data from an outside source with minimal radioactivation time. For example, given a total data acquisition samplefrequency of 5 kHz, the Bionode's radio will transmit 125 data packetsper second and initiate a handshake once every 800 milliseconds. Giventhe radio on-time described above, bidirectional communication isachieved with the radio being deactivated at least 86.7% of the time.

Another challenge in a wireless communication scheme is increasing datarobustness. In order to properly analyze any data recorded by theBionode 820, the ability to identify when data has been corrupted orlost may be desired. Data can be corrupted or lost during wirelesstransmission in various conditions, including: if it is obstructed by ablockage that can absorb RF energy; if a nearby device communicating onthe same frequency creates interference; and if the distance between theBionode 820 and the base station 810 exceeds the transmission range ofthe Bionode 820. Furthermore, data can be lost in the scenario if theBionode 820 suddenly loses power during data acquisition ortransmission.

The Base Station 810 can be configured to employ methods to detect bothcorrupted and lost data packets. For example, before sending datapackets to the base station 810, the Bionode 820 can append a 2-bytecyclic redundancy check (CRC) to the end of the packet (shown in FIG.7). The base station 810 uses this CRC to determine the validity of allincoming data packets. The capability to perform redundancy checking canbe implemented by Bionode packet CRC Checker 816. Corrupted data packetsfailing this CRC are discarded by the base station 810, and not passedon to other users. Additionally, to make lost data packets detectable,the base station 810 can append a 4-byte time stamp at the end ofincoming packets. These time stamps can be used to determine if datasamples are missing from the acquired data stream, and how many datasamples are missing, which can improve accuracy for later data analysisand improve the overall performance of the Bionode platform.

FIG. 9 shows a diagram of an example for circuitry 900 implementingimpedance matching aspects of the wireless implantable device. Theimpedance-matching circuitry 900 can be employed to maximize the amountof power that is transferred to receiving coils of the power managementboard (shown in FIG. 1B). For instance, each coil—represented in FIG. 9as a coil stage 905 including a capacitor C_(coil) 906 and an inductorLcoil 907 coupled in parallel—is connected directly to an impedancematching stage 910 which maximizes its power transfer efficiency.Acquired AC signals are then rectified using a dual-ended rectifier 915to produce positive and negative DC voltages. Both the positive andnegative rectifier outputs are then passed through passive low passfilters 920 to remove high frequency RF noise. Positive and negativepower rails for the Bionode can be generated by regulating the filteredoutputs of the rectifier 915 circuit. Higher voltages that may be neededby the Bionode stimulation circuit can be generated by passing thefiltered rectifier outputs through positive and negative voltage doublercircuits 930.

The AC voltages coupled onto each coil 905 are capable of beingconverted into both positive and negative DC voltages using the fullwave rectifier 915. Subsequently, high amplitude voltages coming out ofthe rectifier 915 are clamped using diodes 916, so as to protectlow-voltage circuitry on the Bionode. Furthermore, to provide stablevoltage rails to the Bionode, resistor-capacitor-based low-pass filters920 are implemented on both the positive and negative rectifier outputsto reduce coupled AC noise from non-idealities present in the rectifier915. The rectified voltages are then fed into regulators 935, 936 toprovide the digital and recording circuitry on the Bionode withaccurate, low ripple voltage supplies. To supply the higher headroomvoltage that may be required by the Bionode's stimulation circuitry,both outputs of the full wave rectifier can be doubled using a boostconverter for the positive output, illustrated as doubler 931, and aninverting charge pump for the negative output, illustrated as doubler932. The outputs of these doubler circuits provide the voltages requiredby the Bionode's stimulation circuitry to drive its constant currentstimulation output.

FIG. 10 shows an example of the packaging process of a wirelessimplantable device (the Bionode, also shown in FIGS. 2C and 2D), via across-sectional view. In a first stage of the illustrated process, afeedthrough cap 1001 containing receptacles for electrodes (the threereceptacles on the right hand side) as well as a connector for theBionode main board (on the left side of the feedthrough cap 1001) isconstructed. Next, the fully assembled Bionode 1002, including its powermanagement board 1007 and main board 1008 in a stacked relationship, areconnected to the feedthrough cap, and a case 1003 is attached to thefeedthrough cap 1001. Also shown are antennas and power supply linesgoing from the power management board 1007 to the main board 1008.Subsequently, a plug 1004 is connected to the outside of the feedthroughcap 1001 to insulate the electrode receptacles from epoxy, which is usedto create a well above the feedthrough cap 1001. Then, the plug 1004 isremoved, and an initial coating of epoxy 1005 is applied around theentire case 1003. Electrode receptacles 1006 are then connected to theelectrode receptacles, and the well above the feedthrough cap 1001 isfilled with silicone 1007. Once the silicone is cured, the entireimplant is coated once again in epoxy which fully encapsulates theimplant.

The resulting encapsulated cylindrical bionode package, shown in FIG.10, can be 3.5 cm long with a diameter of 1.5 cm and weighs 9 grams.This packaging approach illustrated in FIG. 9 can optimize customizationand flexibility in the design and test cycle of the implantable device.Changes in the board shape, size, and architecture can be accommodatedby quick changes to device casing and feedthrough board layout,providing fast turn-around and implementation. In addition, theinterconnects utilized by the feedthrough board can be modified to meetthe ever evolving attributes of future devices such as capacitivefeed-through systems. Moreover, the materials and tools used in thismethod are relatively inexpensive and easy to obtain and adopt.

For devices that do not require any adjustments to the Bionode hardware,the top layer of epoxy surrounding the feedthrough well can be removedusing a band-saw or rotary tool. Once the epoxy is removed, the siliconand leads can be removed by hand. New leads can then be inserted, thewell can be refilled with silicon, and the device can be re-encapsulatedin epoxy. For devices needing adjustments to the Bionode hardware (i.e.devices needing different AFE passband values), the casing can be cutbelow the feedthrough board, and the device can be removed, adjusted,and mounted to a new feedthrough board for repackaging.

Referring to FIG. 11, a flow chart of an exemplary method 1100 ofimplanting a module (implantable Bionode capsule) in a subject is shown.In some embodiments, the module may have features similar to modulesdescribed above with reference to FIGS. 1-10, for example. Method 1100facilitates implantation of a module within a subject, and communicationbetween the module and other system components.

Exemplary method 1100 includes operation 1102 of implanting a module ina subject. The subject may be a human subject or an animal subject. Themodule may be implanted in an internal cavity of a subject such that themodule is completely within the subject (e.g. completely under the skinof the subject with no part of the module directly exposed to theexternal environment).

The module may be implanted at a selected anatomical location. Forexample, operation 1102 may include making an incision proximate aselected implantation location where the module will be secured in thesubject, inserting the module through the incision, securing the module(e.g. using one or more sutures to maintain a selectedorientation/position), and closing the incision. In one example usescenario involving a human patient, the incision may create an openingproximate the patient's collarbone. The module can be inserted throughthe incision and secured subcutaneously within the patient at a chestlocation. In other use scenarios involving a human patient, operation1102 may include implanting the module elsewhere in the chest, abdominalcavity, pelvic cavity, thoracic cavity, dorsal cavity, cranial cavity,extremities of the body, etc. Similar operation procedures and insertionlocations can be used for animals, such as mice.

The anatomical location where the module is implanted may be selectedbased on the anatomical features the module is configured to interactwith. For example, the module may be located proximate to a particularanatomical structure, or between multiple anatomical structures, thatthe module is intended to monitor or stimulate. Implantation in asubcutaneous region of the chest may facilitate an operation 1102 thatis safe and efficient while reducing invasiveness. Implantation in achest location may be suitable for a range of applications or conditionsthat the module may be configured to address, and facilitatecommunication with other system components remotely located within thesubject and/or external to the subject.

Method 1100 includes operation 1104 of implanting a transducer proximatean anatomical structure with which the transducer is configured tointeract (sense or stimulate, for example). The transducer may becommunicatively coupled with the module (wired or wirelessly), such thatelectrical signals may be communicated between the module and thetransducer. In various embodiments, the transducers may include one ormore sensors or electrodes configured for impedance monitoring, thermalmonitoring, pressure monitoring, optical monitoring and/or one or moreoutputs, such as outputs configured to provide electrical or opticalbiomodulation, etc.

Operation 1104 may include securing the transducers to an anatomicalstructure. The anatomical structure may be selected based on a conditionthat the module is configured to monitor or stimulate. For example, atransducer may include a pressure sensor located proximate the bladder(e.g. for urinary incontinence applications), an optical sensorconfigured to measure characteristics of a blood stream (e.g. formeasurements of cytokines, hormones, etc.), an electrical sensor and/oroutput located proximate the vagus nerve, the brain, and sympathetic ortympanic nerves associated with the heart or lungs, etc.

In some embodiments, method 1100 includes operation 1106 of linking themodule and the transducer. For example, operation 1106 may includeconnecting the transducer to the module by a wired lead that physicallyconnect the transducer with the module and allow wired communicationbetween the transducer and the module. The transducer, lead and modulemay be connected to one another prior to insertion within the subject,and subsequently secured at selected locations within the subject. Inother embodiments, the transducers may be connected with the moduleafter the module and/or transducers are implanted within the subject byrouting the lead between the transducer and the module.

In some embodiments, the transducers may include one or more wirelesscommunication components that allow wireless transmission between thetransducer and the module. Operation 1106 may include communicativelylinking the transducer and the module (e.g. after the transducer andmodule have each been secured in a respective selected location) suchthat signals from the transducer may be received by the module and/orvice versa. Accordingly, method 1100 may thus include implanting aplurality of wirelessly communicating devices at locations remote fromone another within a subject (e.g. a module and one or more transducersin wireless communication with the module).

Operation 1106 includes communicatively linking the module andtransducer so that communication and/or processing of transducer outputsmay be performed in real-time. For example, a pressure output from apressure sensor located proximate the bladder may be received andprocessed by the module located in the chest to determine an appropriateresponse. The module may in turn send a response to the transducer orsend associated information to a base station, as described furtherherein.

In some embodiments, method 1100 includes operation 1108 ofcommunicatively linking a base station with the module. Operation 1108may include linking the module and the base station to enable wirelessbidirectional telemetry. For example, operation 1108 may allow datareceived from a transducer to be received and/or processed by themodule, and in turn delivered to the base station. Similarly, operation1108 may allow the base station to deliver data, commands, etc. to themodule.

The base station (for example, the base station 130 shown in FIGS. 1Aand 1B) may have a form factor selected based on the requirements of aparticular application, such as the frequency of communication betweenthe module and base station, and/or the power and processingrequirements of the base station. For example, the base station may beconfigured as a wearable device such as a wristband, bracelet, necklace,earpiece, etc. that may be located proximate a patient's body (e.g.proximate the module) during use. Wearable configurations may facilitatefrequent or continuous communication between the module and the basestation. In other embodiments, the base station may be fixed or remotelypositioned from the patient, and/or configured to communicateintermittently with the module (e.g. once per hour, once per day, etc.).In such configurations, operation 1108 may include linking the modulewith a base station located at a fixed location (e.g. on a bed-sidetable, a treatment location, etc.) or location that may frequently beremote from the user during operation.

With particular regards to embodiments of the base station designed foruse with animal subjects, the base station may comprise a stationarystructure associated with a chamber within which an animal is housed.For example, the base station may be attached to that housing structure,and the wireless power transfer componentry of the base station mayinclude metal components associated with the animal housing.

Referring to FIG. 12, a flow chart of an exemplary method 1200 ofcalibrating a module is shown. In some embodiments, the module may havefeatures similar to modules (namely, “implantable Bionodes”) describedabove with reference to FIGS. 1-10, for example. Method 1200 facilitatescalibration of operational parameters of the module to customizeperformance of the module to the anatomical and physiologicalcharacteristics of the subject (e.g., human subject or animal).

Method 1200 includes operation 1202 of receiving operational data froman implanted module. The data may include stimulus parameters, patientresponse data detected by a transducer, and/or associated data. Forexample, the data may include stimulus parameters including duration,magnitude, profile, etc. of a stimulus delivered to the subject,measured subject response data (e.g. obtained from sensors of one ormore transducers), and/or data from which a subject response to thestimulus may be derived. The module may store, process, and/or transmitthe data received from one or more transducers. Similarly, an external(non-implanted) base station may receive the data (e.g. from theimplanted module) and store, process, and/or transmit the data toanother system component.

Method 1200 includes operation 1204 of transmitting the data to anexternal user device, for example, the computing system 160 shown inFIG. 1 having data acquisition controller software. The data may betransmitted directly to the user device from the external base station,or delivered to the user device via one or more intermediate devices.The user device may process the data to calculate information related tothe performance of the treatment. For example, the user device may beprogrammed to analyze the data to determine optimal or improve stimulusparameters based on the measured patient response to the stimulus.

In an exemplary embodiment, the user device may be a computer, phone,tablet, PDA, etc. that includes a display configured to output the dataand/or related information to an operator, such as a physician ormedical professional, and an input device to receive input from theoperator. The operator may review the stimulus parameters and measuredsubject response to the stimulus, and make a determination regarding theefficacy of the stimulus parameters based at least in part on themeasured subject response to the stimulus. The operator may determinethat one or more stimulus parameters should be adjusted to improvepatient efficacy, safety, etc. Alternatively, the operator may determinethat no changes to the stimulus parameters are necessary (e.g. and thattreatment can continue for a predetermined period of time).

Method 1200 includes operation 1206 of receiving user input related toone or more operational parameters of the implanted module. For example,if an operator determines that one or more stimulus parameters should bechanged, the operator may provide input instructing the system to adjustone or more stimulus parameters. The operator provides input to the userdevice. The input may be subsequently transmitted from the user deviceand received by another system component, such as the base station,module, or other system component.

In an exemplary embodiment in which the base station receives a userinput related to one or more stimulus parameters, method 1200 includesoperation 1208 of transmitting commands to the implanted module toimplement the stimulus parameters instructed by the user. The module mayreceive the stimulus parameters and operate using the updated stimulusparameters (e.g. for a user selected period of time, for a predeterminedperiod of time, or indefinitely until the stimulus parameters aremanually changed). During this period, the system may capture and storepatient response data for analysis by the system or an operator.Operations 1204 and 1206 may be repeated to determine whether thestimulus parameters should be maintained or are optimized for thepatient on an ongoing basis.

Method 1200 can facilitate calibration (e.g. manual calibration) ofsystem parameters based on measured patient response to actual stimulusapplied to the subject. In some embodiments, an initial stimulus may belimited (e.g. in duration, magnitude, profile, etc.) and graduallyincreased until a particular measured subject response is observed. Anoperator may identify stimulus parameters by observing the measuredsubject response in real-time or nearly real-time. Alternatively or inaddition, an operator may observe the measured subject responses over apredetermined duration (e.g. an hour, a day, a week, a month, etc.) atone or more intervals to determine whether the stimulus parametersshould be modified.

In some exemplary embodiments, method 1200 may include operation 1210 ofautomatically adjusting stimulus parameters by the system (e.g.automatically generating a command at the implanted module or externalbase station that adjusts the stimulus parameters) based at least inpart on a measured patient response. For example, the system may beconfigured with a closed-loop control algorithm such that stimulusparameters are adjusted until a desired subject response is attained. Ifthe measured subject response suggests that a stimulus is insufficientto generate the desired subject response, the magnitude, duration,profile, etc. of the stimulus may be increased. Likewise, if themeasured subject response suggests that the stimulus is too great (e.g.too close to a safety threshold), the magnitude, duration, profile,etc.), the stimulus may be decreased. In various exemplary embodiments,operations 1206, 1208, and 1210 may be performed individually (e.g.exclusively manual adjustment or exclusively automatic adjustment),together (e.g. sequentially), or in any desired combination.

The system may be programmed to allow automatic adjustments to thestimulus parameters within a particular range and manual adjustmentsoutside of the particular range. For example, the system mayautomatically refine the stimulus parameters within a relatively narrowrange. The external base station may transmit commands to the implantedmodule to refine the stimulus parameters within a particular range.Relatively larger changes to stimulus parameters may require manualintervention (e.g. at operation 1206). Automatically performingrelatively small changes to the stimulus parameters may improve efficacyby calibrating the stimulus parameters to a particular subject withlittle or no manual intervention. Limiting large changes automaticallymade by the system to the stimulus parameters may promote overall safetyand reliability of the system by requiring manual input from an operator(e.g. a physician or medical professional) in order to make majorchanges to system operation.

Referring to FIG. 13, a flow chart of an exemplary method 1300 ofdelivering a stimulation to a subject is shown using an implantedmodule. In some embodiments, the implanted module may have featuressimilar to modules described above with reference to FIGS. 1-10, forexample. Method 1300 facilitates subject stimulation in response to ameasured condition of the subject.

In an exemplary embodiment, method 1300 includes operation 1302 ofmonitoring a subject condition (or a patient condition, in the case of ahuman subject). For example, an implanted transducer may include asensor for monitoring a condition at an anatomical location, such as asensor configured for impedance monitoring, thermal monitoring, pressuremonitoring, optical monitoring, etc. The transducer may communicate withone or more system components, directly or indirectly, such as theimplanted module and/or external base station that receives, processes,and/or stores the measured subject condition. For example, the measuredcondition may be a pressure proximate a bladder of the subject,electrical activity of a component of the nervous system, or othercondition associated with the health condition of a subject.

Method 1300 includes operation 1304 of identifying a subject event basedat least in part on the measured subject condition. Data related to themeasured subject condition may be communicated from the transducer tothe module and/or base station which may, in turn, process the receiveddata to identify whether one or more subject events are occurring orimminent. For example, the measured subject condition, a derivative ofthe subject condition, or other parameter related to the measuredsubject condition, may be compared to a threshold value indicative ofthe subject event.

Comparison to a threshold value, or processing according to apredetermined relationship, the measured subject condition may be usedto determine the presence of a subject event. In an exemplaryconfiguration, a transducer is implanted proximate the esophagus and/orlarynx, and includes a sensor that outputs a measurement related to anacid level in the esophagus and/or larynx. Operation 1304 may includecomparing the acid level measurement to a predetermined acid levelthreshold considered to be indicative of a reflex that prohibits freebreathing. Accordingly, based at least partially on an acid leveldetermined to be greater than the threshold level (e.g. maintained overa particular period of time), the system identifies a subject breathingevent. Similarly, such acid levels may be used to identify an underlyingcause, such as a seizure, that may be indirectly responsible for theelevated acid levels measured by the transducer.

Operation 1306 includes determining a response to the identified subjectcondition. The system may identify a responsive stimulation configuredto alleviate or reverse the subject event. For example, the system mayidentify a stimulation for delivery to a particular anatomical locationhaving a selected duration, magnitude, profile, etc. based at least inpart on the subject event. After identifying the subject event, the basestation determines the appropriate responsive stimulation and delivers acommand to the module, which in turn delivers a command to a transducer.Alternatively or in addition, the module may process data related to thesubject event to determine the appropriate responsive stimulation anddirectly command a transducer to deliver the responsive stimulation.

In an exemplary embodiment in which the identified subject event is abreathing event or seizure associated with increased acid levels in theesophagus and/or larynx, the system may determine that the appropriateresponsive stimulation is electrical stimulation to nerves connected tothe larynx. Such a response stimulation can relax the larynx and removethe reflex associated with high acid levels, promoting free breathing bythe subject.

Method 1300 further includes operation 1308 of delivering the response.In an exemplary embodiment, the response is executed by one or moreimplanted transducers in response to a command transmitted by theimplanted module. Upon receiving the command from the implanted module,the transducer delivers the responsive stimulation according to receivedstimulus parameters.

In some exemplary embodiments, the implanted module automatically sendsthe command to the implanted transducer. For example, the module and/orbase station may automatically carry out operation 1304 of identifying asubject event, operation 1306 of determining a response, and operation1308 of delivering the response with limited or no manual intervention.Alternatively, one or more operations may require manual intervention,such as by prompting the user for confirmation of a subject event,appropriate response, or delivery of the response. For example, afteroperation 1304 of identifying a subject event, the system may deliver aprompt to the user (e.g. an audio alert, visual alert, haptic alert,etc.) to acknowledge or confirm the subject event. Similarly, afteroperation 1306 of determining a response to the identified condition,the system may deliver a prompt to the user to acknowledge or confirmthe response, and/or allow the user to manually adjust the suggestedresponse. Likewise, before completing operation 1308 of delivering theresponse, the system may prompt the user to acknowledge or confirmdelivery of the response, and/or allow the user to postpone or adjustthe timing of delivery. Accordingly, the system may identify subjectevent and a recommended responsive stimulation that is only deliveredafter manual confirmation of the recommendation is received at a userinput.

Whether the system automatically delivers a responsive stimulation, orrequires manual acknowledgement or confirmation, may be predeterminedbased on the type and severity of a subject event. For example,operation 1308 of delivering the response may be executed without userinput for severe subject events, or subject events that may limit thesubject's ability to timely respond to a prompt. Likewise operation 1308of delivering the response may be postponed until a user confirmation isreceived for minor subject events, events that do not significantlylimit the subject's ability to respond to a prompt, or responsivestimulations that require advanced user awareness.

In some exemplary embodiments, a user may intuitively sense the onset ofa subject condition independent of a prompt delivered by the module,base station, user device, or other component of the system thatcommunicates the subject event to the user. For example, an epilepticsubject may intuitively sense the onset of a seizure independent of ameasured subject condition. Operation 1304 of identifying a subjectevent may include receiving an input from a user that identifies theonset of a subject event, such as by selecting a subject event from amenu of subject events. The system may then proceed to operation 1306 ofdetermining an appropriate responsive stimulation to the manuallyidentified subject event, and operation 1308 of delivering the responsestimulation, as described herein.

Referring to FIG. 14, a flow chart of an exemplary method 1400 ofoperation of the system including an implantable module and an externalbase station that obtains patient input is shown. In some embodiments,the module and base station may have features similar to implantablemodules and base stations described above with reference to FIGS. 1-10,for example. Method 1400 facilitates operation of the implantablemodule, including communication with one or more external devices thatdeliver outputs and receive inputs from a user.

Method 1400 includes operation 1402 of delivering patient event data toa remote device external to the patient. The remote device may be thebase station or a user device, such as a phone, laptop, wearable device,etc. that includes an output and user input device. In an exemplaryembodiment, patient data is wirelessly transmitted from the implantedmodule to the base station, and from the base station to one or moreuser devices.

The patient data transmitted to the remote device may include stimulusparameters, measured patient response data, and/or identified patientevents, etc. In some exemplary embodiments, the module performs limitedor no processing of measured data before forwarding the data to theremote device. The remote device can then process the data to identify apatient event, or manipulate the data into a useful form for observationby the user. Alternatively or in addition, the module may process themeasured data to identify a patient event, and the module may transmit apatient event signal to the remote device indicative of the patientevent.

Method 1400 includes operation 1404 of delivering a patient event promptto the user. The patient event prompt notifies the user that a patientevent has been identified. In an exemplary embodiment, the patient eventprompt includes a visual notification displayed on the remote device.For example, the base station or user device may provide a visualnotification indicating that a patient event has been identified, thetype of patient event, a recommended response, and/or measured patientdata, such as the measured patient data that was used in identifying thepatient event. Alternatively or in addition, the patient event promptmay include an audio, tactile, or haptic alert, for example, that may beunique to a particular patent event or category of patient event.

In an exemplary embodiment, such as system used in a urinaryincontinence application, a patient event may be identified based on apressure measurement obtained from a transducer located proximate thepatient's bladder. In response to elevated bladder pressure, the remotedevice may deliver a prompt to the user indicating the user of theelevated bladder pressure.

In some exemplary embodiments, operation 1404 of delivering a patientevent prompt to the user may be performed at least partially by theimplanted module and transducer. For example, the module may transmit apatient event command signal to a transducer, which in turn generates apatient event stimulation indicative of the patient event. The usersenses the stimulation as an indicator of the patient event. Deliveringa patient event stimulation may provide a relatively more natural userinteraction with the system (e.g. compared to interaction with anexternal remote device). For example, in an embodiment in which bladderpressure is monitored, the module may transmit a patient event commandsignal that generates a patient event stimulation that is perceived bythe user as a full bladder. For example, the patient event stimulationmay generate a sensation that is similar to, or that a user maycorrelate to, the natural sensation of a full bladder.

Method 1400 includes operation 1406 of receiving patient input inresponse to the patient event prompt. For example, a visual patientevent prompt (e.g. on the display of the base station, phone, or otheruser device), may include a menu of user responses. The menu may includean acknowledgement input that allows the prompt to be acknowledged anddismissed, or a response input that allows a responsive stimulation tobe selected. In an exemplary embodiment, the remote device receives thepatient input and transmits the input to the base station and/or moduleto operate according to the received patient input.

Method 1400 includes operation 1408 of transferring power to theimplanted module. In various exemplary embodiments, the implanted moduleincludes a battery configured for periodic wireless recharging. Thebattery is configured to operate for a predetermined period of time(e.g. a day, a week, a month, a year, etc.), and periodically recharge.Operation 1408 may include charging the battery once a day throughinductive charging by positioning the module proximate an appropriatemagnetic field. The magnetic field may be generated by the base stationor another remote charging device. In this way, the module may bepowered while the patient sleeps, for example, or in a manner causingrelatively little interference to the patient's activity.

In some embodiments, operation 1408 is conducted during a discretecharging period, such that operations 1402, 1404, and 1406 may becarried out independently from operation 1408 (e.g. operations 1402,1404, 1406 may be carried out using a stored charge of the battery evenwhen power is not being transferred to the module).

Alternatively or additionally, operation 1408 may include transferringpower to the implanted module simultaneously while one or more otheroperations are being carried out. For example, operation 1408 oftransferring power to the module may include inductively powering themodule via a circulating magnetic field within a wireless poweringtransfer chamber. The circulating magnetic field may be generated by thebase station or another remote charging device. The module may thusreceive power to carry out one or more operations 1402, 1404, 1406, forexample, in substantially real time.

Example Use Case #1—Epilepsy

The systems, devices, techniques, protocols, and processes describedabove and throughout this document can be used in a variety of humanand/or animal applications. In one example use case, they can be used totreat patients with epilepsy. Such treatments can include, for example,stimulating the vagus nerve and deep brain stimulation when particularconditions within the body are detected that indicate a seizure isoccurring or about to occur, providing patients with warnings, such ason a mobile device (e.g., smartphone, smart watch, other wearabledevice) and/or base station, stimulating various nerves and/or systemsto reduce, stop, or prevent seizures a patient is experiencing, and/orother therapeutic monitoring and/or treatment related to epilepsy.

Example implementations for treating epilepsy are described below withregard to FIGS. 15-19. Some or all of these features can be applied tothe treatment of other conditions, as described and/or withmodifications, and/or can be applied to the platform more generally.Additionally, some or all of the descriptions with regard to thetreatment of other conditions described throughout this document can beapplied to epilepsy therapy.

Referring to FIGS. 15 and 16, an example system 1500 is depicted inwhich an implantable system 1504 is configured for the treatment ofepilepsy in a patient 1502. The example implantable system 1504 issimilar to the implantable systems described above, and includes animplantable control device 1506 (also referred to as a “bionode”) andone or more separate sensing and/or stimulating devices 1508 (e.g.,implantable wireless electrodes), which can be wirelessly powered by thecontrol device 1506 (no battery or other locally housed power source inimplantable devices 1508), can wirelessly transmit data to the controldevice 1506, and/or can be wirelessly controlled to dischargetherapeutic stimulation to one or more locations on the patient 1502.Alternatively or additionally, the electrodes may be directly connectedvia leads to the bionode. The system 1500 can provide a toolbox ofimplantable devices with accompanying base station 1530 for wirelesspowering and a graphical user interface (GUI) (e.g., provided on amobile device, like a smartphone or smartwatch) for wirelesscommunication to and from the control device 1506, which can beimplanted in the patient's cortex, for example. The devices that arepart of the system 1500 have the capacity for multi-channel neuralrecording, optical and electrical stimulation, wireless telemetry,wireless powering, and embedded algorithms for closed-loop feedback andstimulation. FIG. 16 depicts a schematic view of an exampleimplementation of the system 1500, with examples of the base station1530, the implantable system 1504, the control device 1506, theimplantable sensing and stimulating devices 1508, a user device 1540providing a GUI and RF telemetry with the control device 1506, andnervous tissue 1522, such as cortical and deep brain tissue to whichtherapy is applied and/or measurements are taken.

The implantable electrodes 1508 in this example include one or moreelectrodes 1520 implanted at particular locations 1522 a-c in thepatient's body, including at the cortex 1522 a, the brainstem/deep brainstructures 1522 b, and the vagus nerve 1522 c. The electrodes 1520 canbe implanted at depths ranged from 2.0 to 7.0 mm. These electrodes 1520can take various measurements at one or more of these locations 1522a-c, which can be wireless transmitted to the control device 1506 foranalysis. These electrodes 1520 can sense and transmit, for example,single neuron measurements, local field potential (LFP), andelectroencephalogram (EEG). These electrodes 1520 can also wirelesslydischarge therapeutic stimulation at one or more of these locations 1522a-c when directed to do so by the control device 1506. Thesestimulations can include, for example, deep brain stimulation (DBS).

In addition to receiving and monitoring conditions related to epilepsyin the patient 1502, determining particular therapeutic stimulation thatshould be provided to the patient 1502, and wirelessly directing one ormore of the electrodes 1520 to deliver the determined therapy, thecontrol device 1506 can include components to provide wireless data andpower (1512) that permits the control device 1506 to wirelessly outputdata to a base station and/or to a mobile device (e.g., smartphone,smart watch), and to be wirelessly powered and/or charged. This outputdata can include a variety of different patient data, such as patientdata, a log of conditions detected and therapies delivered, alerts as tocurrently detected conditions (e.g., oncoming seizure, seizure currentlydetected), and/or other data. The control device 1506 can transmit thisdata wirelessly. The control device 1506 can be powered wirelessly(e.g., via RF signals) and can additionally include a local power source(e.g., battery) that can be charge via the wireless signals and that canpower the control device 1506 when the wireless signal is unavailable.The packaging of the control device 1506 can be, for example, glass.

The control device 1506 include an analog front end 1510 that receiveswireless signals transmitted by the electrodes 1520. The analog frontend 1510 provide the received signals to the signal processing subsystemon the device 1506, which includes a microcontroller 1514 andfield-programmable gate array (FPGA) 1516, which is an integratedcircuit designed to be configured after manufacturing. Signal processingcan be performed on-board or off-board, and can involve using aclosed-loop algorithm 1518, which can be used to identify particularphysiological conditions within the patient 1502 and can determine,based on the particular detected conditions, whether to providebioelectric stimulation at one or more of the locations 1522 a-c. Forexample, the closed-loop algorithm 1518 can be performed by the controldevice 1506, by a device external to the control device 1506 (e.g.,mobile device, base station), or by a combination of the two. When acondition is detected that warrants stimulation, the closed-loopalgorithm 1518 can direct the bioelectric stimulator output unit 1519 toeither directly provide the therapy or to cause one of the electrodes1520 to deliver the therapy. For example, the control device 1506 caninclude on-board components to delivery stimulation therapy, and/or cantrigger one of more of the electrodes 1520 to deliver the therapy.

The closed-loop algorithm 1518 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 1502 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 1502. For example, the closed-loop algorithm1518 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 1502. After being initially calibrated, the closed-loopalgorithm 1518 can continue to learn and adapt over time by analyzingdata generated by the electrodes 1520, therapy provided to the patient1502, and the patient's response to the therapy.

A physiological pathway 1524 that is being monitored as part of thesystem 1500, which includes the patient's cortex, brainstem, vagusnerve, inflammation reflex, and cytokine release. The closed-loopcontrol that is being implemented by the closed-loop algorithm 1518 isdirected toward monitoring and providing therapy related to thephysiological pathway 1524, which includes receiving sensor data fromelectrodes 1520 implanted at the cortex and brainstem, processing thosesignals, and stimulating the vagus nerve to impact and minimize theinflammation reflex when, for example, a seizure is occurring through acytokine release. Cytokine measurement 1526 can be taken using theelectrodes 1520 (e.g., a optrode, as described in greater detail belowwith regard to FIG. 33) and used to determine whether the stimulationwas sufficient to stop the cytokine release (which can occur in somepatients experiencing seizures), and thereby stop/minimize theinflammation reflex. The closed-loop algorithm 1518 can repeatedlymonitor the cytokine levels and apply vagus nerve stimulation whenappropriate until the patient's inflammation reflex has stopped and/ordropped below a threshold level. The closed-loop algorithm 1518 can beautomatically implemented without explicit patient direction.

As indicated by the uppward and downward arrows emanating from the vagusnerve in the physiological pathway 1524, vagus nerve stimulation canprovide multiple paths for epilepsy therapy. For example, the upwardarrow from the vagus nerve to the brainstem and the cortex indicatesthat vagus nerve stimulation can evoke a cortical response that can beused to treat patients experiencing seizure (e.g., stop seizures oncethey are occurring, or prevent them before they begin). The downwardarrow from the vagus nerve to the inflammation reflex, the cytokinerelease, and the cortex indicates that vagus nerve stimulation can evokea different response via cytokine release modulation. As discussed belowwith regard to FIGS. 33-34, vagus nerve stimulation can be used toreduce and/or stop the release of cytokine in the patient, which canreduce inflammation. Recent research has suggested that persistentinflammation in patients over a period of time can cause patients todevelop epilepsy. For example, patients with traumatic brain injuries(TBIs) can experience increased inflammation caused by increase releaseof cytokine following the TBI. This may cause, or contribute to, thepatients developing epilepsy. By stimulating the vagus nerve, cytokinerelease can be reduced and inflammation in a patient can be reduced,which can stop, slow, or mitigate the development of epilepsy.

The system 1500 can deliver electrical stimulations to the patient 1502using appropriate stimulating frequency, waveforms, time delay fromdetection, stimulus current output, and other parameters to deliverneural therapy to allow for clamping the evoked cortical response so asto stop seizures in patients. Such parameters can be patient-specific,and can be developed through data collected during in-clinic/hospitalmonitoring of seizure episodes and the patient response to variouslevels of stimulation therapy. At a behavioral level, wirelessclosed-loop implantable devices included in the system 1500 can use arange of stimulation parameters will allow for multifactorialmodifications to address these complex problems. For example, opsins maybe selectively expressed in cell populations within the hippocampus andstimulation paradigms evaluated to stop seizures from progressing.

For closed-loop epilepsy therapy to be successful, the system 1500 andcontrol device 1506 use a reliable seizure detection feedback algorithm.For example, the device 1506 can use a digital ASIC algorithm isultralow power, reduces the device profile, and is specifically designedfor specialized disease applications. Feedback and detection, though,can be used to detect and treat seizures, but can additionally be usedto detect and treat other conditions. Through the use of a low powermicrocontroller (e.g., microcontroller 1514), custom algorithms can beimplemented. For instance, additional and/or alternative controlalgorithms can be implemented for other conditions, such as forpsychiatric therapy that can observe correlations between a wide rangeof longitudinal behaviors, gamma and theta oscillations, and stimulationparadigms to increase or decrease activity of certain neural populationsin response to the oscillations.

Referring to FIGS. 17A-C, these figures depict the anatomy andprojections of the vagus nerve, and the implant locations of for thesystem 1500. FIG. 17A depicts example locations for implanting thecontrol device 1506 and the electrodes 1520, which are implanted on thebrainstem location 1522 b with an example vagal input electrode 1520 aand an example vagal output electrode 1520 b. FIG. 17B depicts across-section of a human brainstem showing the primary sites of vagalinput (the nucleus tractus solitarii (NTS), or “solitary tract”) andoutput (the dorsal motor nucleus (DMN), or “dorsal nuc. of X”). FIG. 17Cdepicts a summary of NTS efferent projections that impart diffuse, nerveactivation level and rate-dependent effects on central nervous system(CNS) function.

Referring to these FIGS. 17A-C, the vagal nerves are the largest andmost evolved nerves in the human body. They perform mostly sensory andparasympathetic (along with some sympathetic) functions within theautonomic nervous system, using acetylcholine (ACh) as the soleneurotransmitter. The left vagus nerve is a mixed nerve with ˜100,000axons, of which an estimated 65-80% are visceral afferent sensory fiberswith sensory receptors located within the aorta, gastrointestinal tract,heart, lungs and esophagus, among others. The anatomy and projections ofthe vagus nerve is summarized in FIGS. 17A-C. Vagal efferents aremyelinated and originate primarily from the dorsal motor nucleus (DMN)of the vagus. The afferent fibers project primarily to the nucleustractus solitarius (NTS), where diffuse projections convey the visceral(and some somatic) sensory information throughout the CNS, includingareas in the limbic system and cortex that regulate emotion. Many of theafferent fibers participate in autonomic reflexes involved inmaintaining homeostasis and have myelinated projections from the nodoseganglion to the NTS, DMN, area postrema, nucleus cunneatus and themedial reticular formation (The nodose ganglion comprises the somata ofunipolar sensory neurons, with unmyelinated projections inferior to andmyelinated projections superior to the nodose ganglion, respectively).The NTS directly communicates with the reticular formation, areapostrema and DMN; it also indirectly communicates with the thalamus,hypothalamus, amygdala, cingulate gyrus, and orbitofrontal cortex viathe locus coeruleus (LC) and parabrachial nucleus (PB). The NTS projectsto the LC, where effective vagus nerve stimulation is believed to excitenoradrenergic neurons, resulting in norepinephrine release in severalstructures of the limbic system and frontal lobe implicated in temporallobe epilepsy (TLE) and major depressive disorder (MDD). This has alsobeen found to suppress inflammation in the CNS associated withAlzheimer's disease.

The system 1500 can apply stimulation therapy to these brain structures,for example, to address treatment-resistant partial onset seizures,which can help patients with drug-resistant temporal lobe epilepsy (TLE)who can experience significant seizure rate reductions. The system 1500can also apply stimulation therapy for other disorders as well, such asrefractory major depressive disorder (MDD) originated from unexpectedpatient-reported mood improvements, for example. Such therapy can reducecingulate activity, the same effect seen from many successfulantidepressant therapies, and altered blood flow and metabolism inlimbic structures. Other applications of the system 1500 are alsopossible.

The system 1500 implant procedure can be rather straightforward. Undergeneral anesthesia, the control device 1506 housing can be surgicallyimplanted in the left chest wall, the cortex, the brain stem, or otherappropriate structures in the patient 1502. A wireless electrode 1520 a(e.g., helical electrode) can then be wrapped around the left cervicalvagus nerve and secured to surrounding tissue. The device 1506 may beexternally activated and programmed using, for example, a wand-likedevice placed over the location of insertion. Stimulation can be, forexample, intermittent and commonly programmed for 30 seconds ofmonophasic, constant-current stimulation every five minutes. However,individual parameters may be adjusted on a patient-to-patient basis inorder to achieve maximal therapeutic efficacy with minimal side effects.Common side effects, such as dyspnea, cough and hoarseness, can bedependent on the intensity of stimulation, but they may diminish withtime. To minimize patient discomfort, the stimulus intensity can beslowly increased over time (e.g., over two week intervals) until abalance is found between the maximum stimulus intensity and thepatients' willingness to accept any side effects. The control method ofparameter optimization can be complex and time consuming for the patientand physician. Table CHA (below) summarizes an example protocol forstimulus parameter adjustments after implantation. Various device andtherapy parameters, as discussed above, can be adjusted according tothis protocol on a per-patient basis.

TABLE CHA Suggested stimulus parameter adjustment protocol To increaseefficacy To manage side effects 1. ≥2 weeks after implant, increase 1.Reduce, output current output current by 0.25-0.5 mA at 2. Reduce pulsewidth 2-week intervels to maximum tolerated 3. Reduce frequency level,typically 1.0-2.0 mA. 4. Reduce ON time 2. If no response after 1-3months at maximum tolerated output current, gradually increase dutycycle (increase ON time, decrease OFF time)

Vagus nerve stimulation (VNS) therapy with the system 1500 can impartantiepileptic and anti-depressive effects through activation of vagalafferent fibers. This is a logical conclusion, because 1) the device isintended to treat neuronal network-level disorders in the CNS, 2) vagalafferent fibers primarily project to the NTS and onward to the LC, wherea chemical lesion was shown to significantly attenuate VNS-mediatedanticonvulsive activity, and 3) evoked potentials from VNS have beenrepeatedly observed in neural recording/imaging studies. However, theconclusion that VNS works by activating unmyelinated Group C nervefibers of the vagus nerve is not settled, because 1) destruction of Cfibers does not destroy the antiepileptic effect of VNS and 2) stimulifound to be effective in epilepsy are of insufficient strength toactivate the unmyelinated, afferent C fibers. Table CHB below providesan overview of the VNS stimulation parameter settings that can be usedwith the system 1500.

TABLE CHB Overview of available VNS stimulus parameter settingsStimulation Programmable Programming Recommended Typical targetparameters range steps initial values values Output current 0-3.5 mA0.25 mA 0.25 mA 1.0-2 mA Frequency 1-30 Hz¹ 1, 2, 5, 10, 15, 20, 25, 30Hz 20 Hz² 20-30 Hz 30 Hz³ Pulse width 130-1000 μs 130, 250, 500, 750,1000 μs 250-500 μs 250-500 μs Duty cycle 10-100%⁴ Function of signal ON,OFF times 10% 10% Signal ON time 7-60 s 7, 14, 21, 30, 60 s 30 s 30 sSignal OFF time 0.2-180 min⁵ 5-60 min, 5-min steps 5 min 5 min 60-180min, 30-min steps ¹Values below 5 Hz should be avoided. ²In depression.³In epilepsy. ⁴Duty cycles greater than 50% have resulted in nervedamage in laboratory animals (26). ⁵Setting OFF time to 0.0 min turnsoff the pulse generator.

If the effects of VNS are due to activation of specific nerve fibergroups within the vagus nerve, then knowledge of the type, level andrate of nerve fiber activation can be used for advancing the field ofVNS therapy and for discovering candidate symptom- or disorder-linkedbiomarkers suitable for use in closed-loop biomodulation devices, suchas the system 1500. Rather than reporting applied stimulus parametersand the associated effects on symptom severity in VNS studies, the nervefiber activation levels in response to the applied stimulus parameterscan be reported and used in closed-loop biomodulation by the system1500. If the nerve fiber activation level is held constant, then it canserve as a pseudo-independent variable so that researchers caninvestigate the mechanisms of action of VNS in a standardized manner(e.g., biomarker response data can be more easily interpreted andcompared across studies or therapy can be dosed in a standardizedmanner).

Maintaining a fixed nerve activation level can be especially useful forquantifying any symptom- or disorder-linked biomarker level changes inresponse to fixed levels of nerve fiber activation for use by the system1500. Graded cortical responses in response to VNS at different stimulusintensities provide indications of relationships between nerveactivation levels and biomarker responses. For example, observedcortical responses with respect to VNS intensity, instead of nerveactivation level, indicate that the relationship may be patient-specificand cannot be adequately quantified or compared to analogousrelationships observed in different subjects (due to differing nerveactivation properties). If the nerve fiber activation level ismaintained with respect to the maximal level of nerve fiber activationin each subject (e.g., when all fibers are activated), then quantitativeanalyses and comparisons of data from VNS studies becomes feasible.Furthermore, if fixed nerve activation levels can be maintained, thenthe stimulus parameter adjustment/optimization period required of allVNS device recipients is hypothesized to become more efficient andeffective.

An automated strength-duration curve-mapping algorithm, known as theClosed Loop Control System, has been developed as a tool forstandardizing study/data reporting methods and therapy. Closed loopcontrol and its related functionality are disclosed in US Pub2014/0243714 entitled “Method and Apparatus for Closed-Loop Control ofNerve Activation,” the entire contents of which is hereby incorporatedby reference as if set forth in its entirety herein. The Closed LoopControl System rapidly determines all stimulus pulse durations andamplitudes within the programmable range that yield a compound actionpotential (CAP) response of fixed magnitude relative to the maximal CAPresponse that occurs when all fibers of a given type are activated. Themagnitude of a peak in a CAP response is directly proportional to thenumber of activated nerve fibers with similar activation and conductionproperties; given the natural variation in fiber diameters and degreesof myelination, distinct fiber groups can be identified based on themeasured conduction velocity of individual CAP response peaks. When theerror between the desired CAP magnitude (i.e., desired percent maximalactivation) and the observed CAP magnitude (i.e., actual percent maximalactivation) is used as negative feedback to adjust the amplitude orduration of the next applied pulse, then the nerve activationproperty-mapping algorithm becomes a nerve activation clamp. In thelatter implementation, the Closed Loop Control System clamps a nervefiber group of interest to any desired level of activation betweenminimal and maximal activation for research or therapeutic purposes.

Using this approach, patient-specific parameters can be identified byexamining the VNS efficacy as a function of therapy delivered to thepatient as measured by the CAP. This is in contrast with all previousapproaches, which quantify efficacy as a function of current delivered.There is an enormous variability in fiber recruitment, as observed inthe CAP, from an identical current stimulus from patient to patient. Forexample, measurements of the current therapy being delivered to humanpatients implanted with the VNS device can be taken by varying thestimulus parameters to maintain varying degrees of constant CAPactivation of A, B, and C fibers. This can permit simultaneousexploration of the mechanism of action for VNS therapy and improve theclinical efficacy obtained from that therapy. These mappings can beprogrammed into, for example, the microcontroller 1514 and/or the FPGA1516.

VNS for control of epileptic seizures was approved for clinical use in1997 using a device manufactured by Cyberonics, Inc. Despite 15 years ofinvestigative efforts, the exact mechanism of action have been largelyundefined. As discussed above, the vagus nerve is composed of bothmyelinated and unmyelinated fibers and one of the specific unknownfactors is precisely which elements of the nerve are activated bystimulation with various parameter settings of the stimulator. Theknowledge of specific response patterns of the nerve elicited by variousstimulator settings would be very beneficial in helping to assessmechanisms of VNS efficacy. Stimulation of a peripheral or cranial nervewith a mixed fiber population generates a nerve compound actionpotential (CAP) with components from various nerve fiber populations,conducted at different rates. The electrical response due to thesedifferent populations can then be separated by certain recordingtechniques. These techniques have been used in the electrophysiologicalevaluation of peripheral nerves but their extension to cranial nervessuch as the vagus has been limited due to anatomical inaccessibility andproblems of signal-to-noise ratio.

The system 1500 provides a platform to record and analyze compoundactions potentials from the vagus nerve to identify mechanism of actionof VNS in seizure suppression, which can be patient-specific.Furthermore, the system 1500 can be applied in other clinical settingsin which it would be useful to evaluate the physiological integrity ofthe vagus nerve, or deliver other therapies via cranial nervestimulation (e.g. depression or atrial fibrillation). Accordingly, thesystem 1500 provides a reliable and patient-acceptable method ofrecording stimulus-induced action potentials from the human vagus nerveof patients and provides software tools to reliably extract the CAPsignal from background noise and estimate the proportion of neurons ofeach fiber type (i.e. A, B, and C fibers) within the vagus nerve thatfire in response to stimulation from the implanted VNS pulse generator.

Patient-specific responses can be analyzed using data recorded inresponse to applied stimulations. For example, a learning algorithm(e.g., closed loop algorithm 1518) can estimates the type and proportionof neurons within the vagal nerve that ‘fire’ each time the implantedpulse generator turns on, yielding insight into which neurons areimportant for effective therapy. This technique can also predict theneurons that will fire when more or less intense stimuli are applied,but only the former software function will be tested. To perform theformer function, the learning algorithm locates, aligns, and averagesthe individual compound action potential responses to stimulation toenhance the quality of the signal. Specific peaks within the signal arethen located, measured and classified along with the implanted pulsegenerator settings. This information is compared to data from otherpatients or data taken from the same patient to determine the type andproportion of neurons that ‘fire’ each time the stimulator turns on. Thepulse generator settings will not be altered in any way during themeasurement and signal processing routines. In this manner, data andmappings can be generated showing:

-   -   Variability in therapy as measured by the CAP rather than        stimulator current output, delivered to patients currently        implanted    -   Correlation between therapy delivered, relative A, B, and C        fiber recruitments as a result of existing stimulus parameters,        and reported efficacy over time

Referring to FIG. 18, which depicts a cardiocentric view of theautonomic neuronal hierarchy that coordinates regional cardiac indexesas they related to the CNS. Anatomically, the heart is innervated bydiverse nerve plexi, such as sensory, motor (sympathetic andparasympathetic efferent) and interconnecting nerves to communicate withextracardiac and intracardiac ganglia. FIG. 18 shows a conceptualdiagram of a hierarchical neural structure based on more than a centuryof study on cardiac neural regulations. As shown in the figure, theintrathoracic extracardiac ganglia contain not only cardiac sympatheticefferent postganglionic neurons but also cardiac afferent neurons andlocal circuit neurons. Similarly, Intrinsic cardiac ganglia containsensory and local circuit neurons as well as sympathetic andparasympathetic efferent postganglionic neurons. These neurons and theirinteractions are under the tonic influence of central (medullary andspinal cord) neurons. The functional implication of such a complexinterconnection has only been studied with limited capability, largelydue to a prior inability to study neural function in its working state.In addition to controlling normal physiology, cardiac autonomic nervesalso play roles in arrhythmogenesis. For example, pulmonary veins havemuscle sleeves that extend from the left atrium, along with projectionsfrom the vagus nerve. The pulmonary vein and left atrial junction arerichly innervated by both sympathetic and parasympathetic fibers, andthese two branches of the autonomic nervous system are highlyco-located. These cardiac autonomic nerves could be identified byspecific immunohistochemical staining, such as tyrosine hydroxylase forsympathetic nerves and cholineacetyltransferase for parasympatheticnerves. Acetylcholine-mediated atrial fibrillation (AF) can befacilitated by isoproterenol infusion, which decreases the acetylcholineconcentration for AF induction and increased AF duration.

Sympathetic nerves primarily originate from the upper fourth and fifthsegments of thoracic spinal cord and innervate the heart by passingthrough the superior cervical ganglion, the middle cervical ganglion,and the stellate ganglion. The sympathetic nerves from the superiorcervical ganglia and the stellate ganglia communicate primarily withC1-3 and C7-8 and T1-2, respectively. The superior, middle and inferiorcardiac nerves follow along large vessels such as the brachiocephalictrunk, common carotid and subclavian arteries. They join with cardiacbranches from the vagus nerve and form the cardiac plexus. Theparasympathetic nerves innervating the heart originate from the vagusnerve. The cardiac branches of the vagus nerve converge with ganglioncells in the cardiac plexus or intracardiac ganglia within epicardialfat pads. Intracardiac ganglionated plexi are a complex of intrinsiccardiac neurons connecting with extracardiac nerve structures and atrialand ventricular tissue. They function as final coordinator influencingcardiac mechanical and electrical indices. For example, the right atrialganglionated plexus (RAGP) innervates the sinoatrial node and theinferior right ganglionated plexi innervates the AV node. The functionof these two GPs as “integration centers” for an extrinsic autonomicnervous system to modulate SA node and AV node, respectively. Also,ablation of these GPs could eliminate effective refractory periodshortening and reduce AF inducibility during sympathovagalco-stimulation. GP stimulation using the system 1500, for example, canfacilitate converting pulmonary vein firing into AF. The superior leftganglionated plexi (SLGP) located between pulmonary vein and the leftatrial appendage, is another intrinsic nerve structure known to containboth sympathetic and parasympathetic nerves. The ligament of Marshall(LOM) derives from the embryonic left superior vena cava and is known tocontain both nerve and muscle fibers. Sympathetic nerves from the middlecervical and stellate ganglia passes along the LOM to innervate the leftventricle. Parasympathetic nerve fibers from vagus nerve traverse LOM toinnervate left atrium, left pulmonary veins, coronary sinus andposterior LA fat pads.

Neural control of cardiac function has been studied for over a century.However, the fact that cardiac autonomic regulation involves, inaddition to central commands, peripheral autonomic activity wasunderstood only recently. The system 1500 can be used to generatefurther insights into these effects. In order to understand the nervetraffic, high-definition methods, such as those described above andbelow with regard to 1500, capable of simultaneous recording frommultiple distributed sites can be used. For example, the system 1500 canbe used to simultaneously monitor multiple locations to understand theactivation and propagation of these nerve activities, and to associatethe nerve activities with AF vulnerability. These high-definitionmeasurement will allow testing of the hypothesis that sympathovagalco-activation involves a feedback mechanism between the stellateganglion and the middle cervical ganglion, and based on the results,stimulation and therapeutic applications via the system 1500. Thefeedback can be provided through the neural connections between thestellate and the middle cervical ganglia. Such evaluation can include,for example:

-   -   Increasing the number of observation sites to allow better        characterization of the neural activities and neural traffic        from different areas of origin.    -   Increasing the bandwidth and sampling rate of nerve signals to        allow deconvolution of nerve bundle and ganglion local field        potentials into more functionally homogeneous groups.    -   Modulating recruitment of vagus nerve fibers during VNS therapy        to decrease the incidence of atrial fibrillation.

The system 1500 permits integrating signal processing and featureextraction algorithms on-board implantable medical devices, such as thecontrol device 1506. This eliminates or reduces the need for wirelesstransfer of data outside the patient. Effective prediction or detectionalgorithms can be used to implement closed-loop treatment devices thatdeliver electrical, optical, or pharmacological stimulus upon detectionof a physiological event of interest.

In the context of therapeutic devices, such as the system 1500, signalprocessing allows for integrating responsive detection or predictionalgorithms to analyze recorded physiological data and applyinterventional therapy in a temporally specific manner. While there havebeen a number of different approaches proposed to both predict anddetect events, barely a handful of these algorithms are employed inportable computing devices, whether implantable (e.g., 1506) orhand-held (e.g., 1540).

The system 1500 can implement control algorithms that, responsivestimulation of the descending vagus nerve fibers, can modulate atrialfibrillation and other conditions (e.g., seizure), and can dramaticallyreduce hospitalizations in the US and worldwide.

The system 1500 and the control device 1506 can implement eventdetection algorithms to make them feasible in implantable applications,such as through low-power digital design techniques allowing forcustomizable digital designs to implement the detection algorithms at acost several times lower than employing standard micro-controllers ordigital signal processors. For example, the system 1500 can use a customfeature extraction processor to transmit relevant markers of events,which can reduce the amount of time a wireless transmitter would need tobe powered and can improve the power when feature extraction wasapplied. The RF components of the system 1500 can consume the most powerwhen operated—sometimes an order of magnitude more than the rest of thesystem. With the need to transmit through longer distances and throughskin and tissue, RF transmission schemes may need to be more robustwhile still remaining low-power. For neural prostheses as part of thesystem 1500, integrating event detection and/or prediction algorithms onboard the implant 1506 eliminates the need to transmit any data outsideof the implant besides programming and housekeeping information duringstartup.

Two general methods can be used as part of the system 1500 to extractmeaningful information from neural data-analog and digital.Traditionally, analog schemes are thought of to be more power hungry,although there have been low-power implementations of analog featureextraction circuits proposed lately. Analog circuit techniques do notrequire an ADC to accurately digitize neural signals—a challengingdesign given the dynamic range of neural signals.

FIG. 19 shows a block diagram of the possible feature extraction schemesthat can be applied to implantable medical devices, such as part of thesystem 1500. The system 1500 can use an analog signal encoding scheme,for example, that uses a one-bit comparator to threshold (spike detect)data, reducing the neural signal to digital spike orthreshold-crossings. The value of the chosen amplitude threshold iscritical in deciding the efficacy of this technique. This simpledigitization scheme is justified by the fact that most neuroprostheticapplications only require timing information from spikes (actionpotentials) accurate to about 1-ms. Additional and/or alternativeencoding and detection schemes can be used.

Digital schemes included with the system 1500 can be implemented at lowhardware costs and can integrate maximal functionality per unit siliconarea occupied especially with scaled technologies. Given that medicalimplants normally do not demand high clock-speed performance, thedigital designs of the system 1500 can also allow for severe voltagescaling operating in near to sub-threshold regions of operation. Forexample, a computationally efficient digital implementation of anevent-based detection algorithm for the system 1500 can be operated at avoltage as low as 300-mV with less than 350-nW of power consumption perchannel. The selection of features for the system 1500 and the controldevice 1506 for implementing an algorithm can be suitable forwirelessly-powered devices and/or battery-powered devices.

Using these approached in a manner similar to our prior work in seizuredetection, this same techniques and system components can be applied tolower the mortality rate of SUDEP, and reducing the number ofhospitalizations from atrial fibrillation, as described below.

Example Use Case #2—Sudden Unexpected Death in Epilepsy (SUDEP)

The systems, devices, techniques, protocols, and processes describedabove and throughout this document can be used in a variety of humanand/or animal applications. In one example use case, they can be used totreat patients with epilepsy to prevent SUDEP, which is a fatalcomplication of epilepsy defined as the sudden and unexpected,non-traumatic and non-drowning death of a person with epilepsy, withouta toxicological or anatomical cause of death detected during thepost-mortem examination. The specific causes of SUDEP are not preciselyknown, but appear to be multifactorial and include respiratory, cardiacand cerebral factors, as well as the severity of epilepsy and seizures.Possible pathophysiological mechanisms of SUDEP include seizure-inducedcardiac and respiratory arrests. Treatments to prevent SUDEP in patientscan include, for example, stimulating the vagus nerve when particularconditions within the body are detected that indicate a possible SUDEPcondition, providing patients with warnings, such as on a mobile device(e.g., smartphone, smart watch, other wearable device) and/or basestation, stimulating various nerves and/or systems to reduce theincident of acid reflux that may occur while a patient is experiencing aseizure, and/or other therapeutic monitoring and/or treatment related toepilepsy.

Example implementations for preventing SUDEP are described below withregard to FIG. 20. Some or all of these features can be applied to thetreatment of other conditions, as described and/or with modifications,and/or can be applied to the platform more generally. Additionally, someor all of the descriptions with regard to the treatment of otherconditions described throughout this document can be applied epilepsytherapy.

Referring to FIG. 20, an example system 2000 is depicted in which animplantable system 2004 is configured for the treatment of epilepsy in apatient 2002. The example implantable system 2004 is similar to theimplantable systems described above, and includes an implantable controldevice 2006 (also referred to as a “bionode”) and one or more separatesensing and/or stimulating devices 2008 (e.g., implantable wirelesselectrodes), which can be wirelessly powered by the control device 2006(no battery or other locally housed power source in implantable devices2008), can wirelessly transmit data to the control device 2006, and/orcan be wirelessly controlled to discharge therapeutic stimulation to oneor more locations on the patient 2002. The system 2000 can provide atoolbox of implantable devices with accompanying base station 2030 forwireless powering and a graphical user interface (GUI) (e.g., providedon a mobile device, like a smartphone or smartwatch) for wirelesscommunication to and from the control device 2006.

The implantable electrodes 2008 in this example include one or moreelectrodes 2020 implanted at particular locations 2022 a-c in thepatient's body, including at the cortex 2022 a, the brainstem 2022 b,the vagus nerve 2022 c, the respiratory system 2022 d, and/or otherlocations. For example, the electrodes 2020 can be implanted in thebrainstem 2022 b (e.g., hippocampus, pre-Botzinger, nucleus ambiguus,nucleus tractus solitarius, and rostral and caudal ventral-lateralmedulla (VLM)) to detect local field potential and single and multiunitactivity for evidence of seizures propagating into, or silencing,brainstem structures. These electrodes 2020 can take variousmeasurements at one or more of these locations 2022 a-c, which can bewired and/or wireless transmitted to the control device 2006 foranalysis. These electrodes 2020 can sense and transmit, for example,electric physiological conditions including single neuron measurements,LFP, EEG, electrocardiogram (ECG), and electromyogram (EMG). Theseelectrodes 2020 can also wirelessly discharge therapeutic stimulation atone or more of these locations 2022 a-c when directed to do so by thecontrol device 2006. This stimulations can include, for example, deepbrain stimulation (DBS) and/or nerve stimulation.

In addition to measuring electric physiological conditions using theelectrodes 2020, the implant system 2006 can use one or more sensors2016 to measure mechanical and/or chemical conditions within the patient2002. For example, the sensors 2016 can measure and provide data onmechanical physiological conditions including respiratory conditions(e.g., rate of respiration) and patient temperature. The sensors 2016can also measure and transmit chemical conditions including pH in thepatient's body. The sensors 2016 can be, for example, transducers. Suchsensors 2016 can be either directly or indirectly (via leads) connectedto particular physiological structures in the patient's body, such asECG leads on the chest wall; EMG leads to diaphragm or other muscle;and/or thermocouple implanted in the nasal passage.

In addition to receiving and monitoring conditions related to SUDEP inthe patient 2002, determining particular therapeutic stimulation thatshould be provided to the patient 2002, and wirelessly directing one ormore of the electrodes 2020 to deliver the determined therapy, thecontrol device 2006 can include components to provide wireless data andpower (2012) that permits the control device 2006 to wirelessly outputdata to a base station and/or to a mobile device (e.g., smartphone,smart watch), and to be wirelessly powered and/or charged. This outputdata can include a variety of different patient data, such as patientdata, a log of conditions detected and therapies delivered, alerts as tocurrently detected conditions (e.g., oncoming seizure, seizure currentlydetected), and/or other data. The control device 2006 can transmit thisdata wirelessly. The control device 2006 can be powered wirelessly(e.g., via RF signals) and can additionally include a local power source(e.g., battery) that can be charge via the wireless signals and that canpower the control device 2006 when the wireless signal is unavailable.The packaging of the control device 2006 can be, for example, glass.

The control device 2006 includes an analog front end 2010 that receiveswireless signals transmitted by the electrodes 2020. The analog frontend 2010 provide the received signals to the signal processing subsystemon the device 2006, which includes a microcontroller 2014 and a FPGA.Signal processing can be performed on-board or off-board, and caninvolve using a closed-loop algorithm 2018, which can be used toidentify particular physiological conditions within the patient 2002 andcan determine, based on the particular detected conditions, whether toprovide bioelectric stimulation at one or more of the locations 2022a-c. For example, the closed-loop algorithm 2018 can be performed by thecontrol device 2006, by a device external to the control device 2006(e.g., mobile device, base station), or by a combination of the two.When a condition is detected that warrants stimulation, the closed-loopalgorithm 2018 can direct the bioelectric stimulator output unit 2018 toeither directly provide the therapy or to cause one of the electrodes2020 to deliver the therapy. For example, the control device 2006 caninclude on-board components to delivery stimulation therapy, and/or cantrigger one of more of the electrodes 2020 to deliver the therapy.

The closed-loop algorithm 2018 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 2002 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 2002. For example, the closed-loop algorithm2018 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 2002. After being initially calibrated, the closed-loopalgorithm 2018 can continue to learn and adapt over time by analyzingdata generated by the electrodes 2020, therapy provided to the patient2002, and the patient's response to the therapy.

A physiological pathway 2024 that is being monitored as part of thesystem 2000, which includes the patient's cortex, brainstem, vagusnerve, upper esophageal sphincter (UES) and/or larynx, and laryngospasm.The closed-loop control that is being implemented by the closed-loopalgorithm 2018 is directed toward monitoring and providing therapyrelated to the physiological pathway 2024, which includes receivingsensor data from electrodes 2020 implanted at the cortex and brainstemand the electrodes 2016 positioned to measure respiratory andtemperature information, processing those signals, and stimulating thevagus nerve to impact and minimize the inflammation reflex when, forexample, possible SUDEP conditions are detected. Measurements can betaken by the electrodes 2016 and 2020, and can be used to determinewhether the stimulation was sufficient to mitigate the detectedcondition (which can occur in some patients experiencing seizures), andthereby stop/minimize the condition that may indicate the onset ofSUDEP, such as an inflammation reflex the closes the UES and/or larynx.The closed-loop algorithm 2018 can repeatedly monitor patient data andapply vagus nerve stimulation when appropriate until the patient's SUDEPcondition (e.g., UES inflammation reflex) has stopped and/or droppedbelow a threshold level. The closed-loop algorithm 2018 can beautomatically implemented without explicit patient direction.

The closed-loop VNS therapy provided by the system 2000 in response to,for example, alterations in cardiac or respiratory rate has thepotential to reduce the incidence of SUDEP. Other factors andalterations in other factors can additionally and/or alternatively beused to identify the onset of SUDEP and to prevent SUDEP in a patientby, for example, reducing the UES inflammation reflex via stimulation.

The system 2000 take a variety of patient factors into account as partof the closed-loop algorithm, including biological factors of sex andcorrelations with strain on seizures and their consequences. Strainand/or sex in subjects (e.g., animals) may have an impact on SUDEP,factors which can be evaluated separately and/or using an epilepsy model(kainic acid and TeNT). Seizure number and duration can be covariates ofSUDEP, and primary measurements can be of the extent and duration ofpostictal changes in heart rate and postictal changes in respiration.Statistical analysis can assess the impact on the measurements of timeafter injection, and of numbers, durations and semiologies of seizures.SUDEP risk associated with these factors can be evaluated by examiningwhether SUDEP incidents are distributed randomly amongst the factors(strain and sex). In another example, the latter analysis can includeEMG and nasal temperature as indicators of obstructive apnea. Given thesubstantial difference in seizure durations in the acute kainic acidstatus model and chronic experimental epilepsy, other mechanisms,including interactions of cardiac and respiratory dysfunctions can beevaluated as the cause of SUDEP.

The system 2000 can additionally and/or alternatively evaluate thecardiac and respiratory consequences of intrahippocampal injection oftetanus toxin and kainic acid when identifying SUDEP conditions. TheTeNT model may not cause status epilepticus at induction and results inlittle or no neuronal loss in >70% of cases. The kainic acid model maynot cause status epilepticus in subject (e.g., animals) at induction andreliably results in gross neuronal loss in the hippocampus. This canprovide for reliable induction of chronic epilepsy in the kainic acidmodel and works well for the tetanus toxin model too. It has theadvantages of avoiding residual effects of general anesthesia withisoflurane, and can provide baseline pre-induction data and thereforereduce the between-animal sources of variation. Outcome measures caninclude the extent and duration of postictal tachycardia, arrhythmias,hyperventilation, apneas and sudden deaths.

The system 2000 can provide a platform to identify unit and local fieldpotentials associated with seizure-related changes in heart rate,respiration, arrhythmias and apneas. Temporal relationships between unitactivity and postictal cardio-respiratory changes will shed light onmechanism. E.g., tachycardia continuing long after cessation ofpostictal changes in neuronal activity in cardiac centers (notably VLM)would implicate an endocrine component. To be able to detect anyseizure-like activity propagating into the brainstem, recordings will bemade wider band than is conventional for unit recordings. Off-linefiltering can be implemented to help isolate unit activity.

Example Use Case #3—Urinary Incontinence

The systems, devices, techniques, protocols, and processes describedabove and throughout this document can be used in a variety of humanand/or animal applications. In one example use case, they can be used totreat patients with urinary incontinence by stimulating the pelvicnerve. For example, since micturition can be evoked in response toexogenous bladder filling, urodynamic measurements can be made andpelvic nerve stimulation can be tracked to identify relevant functionalresponses, including urinary voiding. A variety of configurations arepossible to identify such voiding conditions, including using balloonpressure sensors into the uterus and colon, recording EMG activity fromthe abdominal wall to investigate the possibility of off-target effectsof pelvic nerve stimulation, measuring temperature in the nerve bundleduring prolonged periods of high frequency stimulation, and/or others,as well as combinations thereof.

Example implementations for urinary incontinence are described belowwith regard to FIGS. 21-32. Some or all of these features can be appliedto the treatment of other conditions, as described and/or withmodifications, and/or can be applied to the platform more generally.Additionally, some or all of the descriptions with regard to thetreatment of other conditions described throughout this document can beapplied urinary incontinence therapy.

Referring to FIG. 21, an example system 2100 is depicted in which animplantable system 2104 is configured for the treatment of urinaryincontinence in a patient 2102. The example implantable system 2104 issimilar to the implantable systems described above, and includes animplantable control device 2106 (also referred to as a “bionode”) andone or more separate sensing and/or stimulating devices 2108 (e.g.,implantable wireless electrodes), which can be wirelessly powered by thecontrol device 2106 (no battery or other locally housed power source inimplantable devices 2108), can wirelessly transmit data to the controldevice 2106, and/or can be wirelessly controlled to dischargetherapeutic stimulation to one or more locations on the patient 2102.The system 2100 can provide a toolbox of implantable devices withaccompanying base station 2130 for wireless powering and a graphicaluser interface (GUI) (e.g., provided on a mobile device, like asmartphone or smartwatch) for wireless communication to and from thecontrol device 2106, which can be implanted in at one or more locationsin the patient's body, for example. The devices that are part of thesystem 2100 have the capacity for multi-channel neural recording,optical and electrical stimulation, wireless telemetry, wirelesspowering, and embedded algorithms for closed-loop feedback andstimulation.

The implantable electrodes 2108 in this example include a cuff electrodeor single neuron electrodes implanted at a location 2122 a thatcorresponds to the patient's pelvic nerve, a pressure and/or temperaturesensor implanted at a location 2122 b corresponding to the patient'sbladder, and/or other electrodes and transducers implanted at or aroundthe locations 2122 a-b, such as external urethral sphincter (EUS) EMGelectrodes, a urine drop counter, and/or other electrodes. The controldevice 2106 can be implanted at any of a variety of locations, such asthe locations 2122 a-b and/or the location 2122 c corresponding to thepatient's PAG. The control device 2106 includes an on-board compoundnerve action potential (CNAP) device that can simultaneously record as abioelectric input analog front end 2116 and can provide nervestimulation as a bioelectric stimulator output 2119.

The electrodes 2120 can take various measurements at the locations 2122a-b, which can be wireless transmitted to the control device 2106 foranalysis. The electrodes 2120 can sense and transmit, for example,bladder response to pelvic nerve stimulation, which can also receive theCNAP input from the on-board bioelectric input analog front end 2116.

In addition to receiving and monitoring conditions related to urinaryincontinence in the patient 2102, determining particular therapeuticstimulation that should be provided to the patient 2102, and wirelesslydirecting one or more of the electrodes 2120 and/or the bioelectricstimulator output 2119 to deliver the determined therapy, the controldevice 2106 can include components to provide wireless data and power(3322) that permits the control device 2106 to wirelessly output data toa base station and/or to a mobile device (e.g., smartphone, smartwatch), and to be wirelessly powered and/or charged. This output datacan include a variety of different patient data, such as patient data, alog of conditions detected and therapies delivered, alerts as tocurrently detected conditions (e.g., oncoming inflammation, inflammationreflex currently detected), and/or other data. The control device 2106can transmit this data wirelessly. The control device 2106 can bepowered wirelessly (e.g., via RF signals) and can additionally include alocal power source (e.g., battery) that can be charge via the wirelesssignals and that can power the control device 2106 when the wirelesssignal is unavailable. The packaging of the control device 2106 can be,for example, glass.

The control device 2106 includes an analog front end 2110 that receiveswireless signals transmitted by the electrodes 2120. The analog frontend 2110 provide the received signals to the signal processing subsystemon the device 2106, which can include a microcontroller 2114. Signalprocessing can be performed on-board or off-board, and can involve usinga closed-loop algorithm 2118, which can be used to identify particularphysiological conditions within the patient 2102 and can determine,based on the particular detected conditions, whether to providebioelectric stimulation of the pelvic nerve (location 2122 a). Forexample, the closed-loop algorithm 2118 can be performed by the controldevice 2106, by a device external to the control device 2106 (e.g.,mobile device, base station), or by a combination of the two. When acondition is detected that warrants stimulation, the closed-loopalgorithm 2118 can direct the bioelectric stimulator output unit 2119 toeither directly provide the therapy or to cause one of the electrodes2120 to deliver the therapy to the pelvic nerve. For example, thecontrol device 2106 can include on-board components to deliverystimulation therapy (CNAP device 2119), and/or can trigger one of moreof the electrodes 2120 to deliver the therapy.

The closed-loop algorithm 2118 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 2102 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 2102. For example, the closed-loop algorithm2118 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 2102. After being initially calibrated, the closed-loopalgorithm 2118 can continue to learn and adapt over time by analyzingdata generated by the electrodes 2120, therapy provided to the patient2102, and the patient's response to the therapy.

A physiological pathway 2124 that is being monitored as part of thesystem 2100, which includes micturition center, PAG, bladder, the pelvicnerve, the lower GI, and urinary voiding. The closed-loop control thatis being implemented by the closed-loop algorithm 2118 is directedtoward monitoring and providing therapy related to the physiologicalpathway 2124, which includes receiving sensor data from electrode 2120implanted at bladder, processing those signals in combination with theCNAP signals, and stimulating the pelvic nerve to minimize instances ofurinary incontinence, for example, when the patient 102 is experiencinginvoluntary urinary voiding. The closed-loop algorithm 2118 canrepeatedly monitor the urinary flow measurements 2126 and can applypelvic nerve stimulation when appropriate until the patient's urinaryvoiding has subsided and/or dropped below a threshold level. Theclosed-loop algorithm 2118 can be automatically and repeatedlyimplemented without explicit patient direction.

The system 2100 can deliver electrical stimulations to the patient 2102using appropriate stimulating frequency, waveforms, time delay fromdetection, stimulus current output, and other parameters to deliverneural therapy to allow for clamping the urinary tract response so as tomodify the patient's urinary incontinence symptoms. Such parameters canbe patient-specific, and can be developed through data collected duringin-clinic/hospital monitoring of seizure episodes and the patientresponse to various levels of stimulation therapy.

FIG. 22 shows in more detail, the anatomical relationship between pelvicnerve and bladder and the localization of sensors and electrodes placedin the bladder, external urethral sphincter and pelvic nerve.

FIG. 23 show example silver hook electrode assemblies used forstimulation and recording from the pelvic nerve, which can allow for adetermination of the bladder response to pelvic nerve stimulation andcan provide a benchmark against which to compare cuff electrodes, asdepicted in FIG. 24. For example, bipolar cuff electrodes (platinumiridium wire with cobalt core in silicone epoxy) can be used on thepelvic nerve routinely in both acute experiments and for chronicimplantation in conscious patients. Cuffs can be implanted, for example,onto the preganglionic nerve trunk with leads tunneled subcutaneouslyand exteriorized to the nape of the neck for tethered stimulation.

In preclinical testing, it was found that stimulation of the pelvicnerve unilaterally using rectangular pulses evoked graded increases inbladder pressure (FIG. 25). In preliminary experiments (n=3) theeffectiveness of low frequency pelvic nerve stimulation was tested inorder to assess the functional integrity of the nerve-bladder projectionfollowing surgery. In line with data from others, brief trains (10 s) oflow frequency stimulation evoked a phasic increase in bladder pressurereflecting contraction of the detrusor (FIG. 25). The effect wasdependent on both the intensity (FIG. 25b ) and the duration (FIG. 25).At low intensities (1-2V), each pulse evoked a twitch-like response inthe EUS EMG (latency=16-18 ms) (FIG. 25d ). As the stimulation intensityincreased, twitch responses were superimposed on tonic EMG activity(FIG. 25e and FIG. 25f ). Tonic EMG activation was not secondary toincreased bladder pressure (FIG. 25e and FIG. 25f ). Occasionally, asingle drop of urine was expelled from the urethra during low frequencystimulation but co-ordinated voids (see below) were never evoked by thisprocedure.

Multi-unit activity was recorded from postganglionic nerve bundlesduring voiding evoked by infusion of saline into the bladder. Whenrecording from the whole nerve bundle the signal to noise ratio duringwas not usually great enough to enable clear distinction of spikeactivity (FIG. 26). However, by carefully splitting the nerve, clearvoiding-related activity could be recorded from some fibre bundles(FIGS. 26B and C and FIG. 27). In some cases, a clear linearrelationship between bladder pressure and nerve activity was present(FIG. 28). In other cases nerve activity was time locked to thecontraction phase of the void rather than bladder pressure per se—firingceased at the time of the sharp drop in pressure as the bladder startedto relax.

During preclinical testing, saline was infused continuously into thebladder to evoke repeated voiding. During the filling phase bladderpressure rose slowly until a threshold pressure was reached, upon whichtime bladder pressure rose steeply, signalling in imminent void. Duringthis time tonic activity in the external urethral sphincter (EUS)increased significantly (FIG. 29a ) and then switched to a burstingpattern (approx. 8 Hz, FIG. 29b ) during which time urine was expelled.During the expulsion phase ‘ripples’ could be seen on the bladderpressure trace, in phase with rhythmic sphincter activity, reflectingback pressure transmitted to the bladder as the detrusor contractsagainst the intermittently closed sphincter.

Stimulation of the pelvic nerve (preganglionic bundle) using highfrequency charge balanced alternating current (sine) initiated within1-2 s of the steep rise in bladder pressure signaling an imminent voidwas able to suppress urine output completely (FIG. 29a-c ). The effectwas readily reversible and voiding resumed within a few minutes ofterminating pelvic nerve stimulation (FIG. 29a ). The bladdercontraction was aborted and tonic activity in the EUS increased (FIG.29c ). Stimulation during the filling phase in between voids (FIG. 29d )had no effect on bladder pressure but evoked tonic activity in the EUS.The effect of pelvic nerve stimulation on voiding was frequencydependent. In different animals optimal suppression of voiding occurredat frequencies between 1 and 3 kHz. There was a non-monotonicrelationship between frequency and efficacy of inhibiting voiding (FIG.30). At sub-optimal stimulation parameters, voiding was sometimessuppressed incompletely or alternatively, a void occurred but wasdeferred until late on in the 60 s stimulation period.

The effect of pelvic nerve stimulation on voiding was frequencydependent. In different animals optimal suppression of voiding occurredat frequencies between 1 and 3 kHz. There was a non-monotonicrelationship between frequency and efficacy of inhibiting voiding (FIG.30). At sub-optimal stimulation parameters, voiding was sometimessuppressed incompletely or alternatively, a void occurred but wasdeferred until late on in the 60 s stimulation period. Stimulation ofeither the right or left pelvic nerve appeared to be equally effective.Bilateral stimulation was no more effective than stimulating the pelvicnerve on one side.

In evaluating the mechanism underlying pelvic nerve-evoked suppressionof voiding, cutting the pelvic nerve contralateral to the stimulatedside (FIG. 31a ) did not suppress repeated voiding evoked by infusion ofsaline into the bladder (FIG. 31b,c ). Neither did it prevent thesuppression of voiding evoked by stimulation of the ipsilateral nerve(FIG. 31d ). When stimulation was carried out during the filling phasein between voids, tonic activity in the EUS and the transienton-response in bladder pressure persisted (FIG. 31e ).

In another series of experiments, the pelvic nerve distal to thestimulating electrode was ligated (FIG. 32a ). Ligation rather thansection was preferred since cutting the nerve inevitably lead tomovement of the central end relative to the nerve cuff electrode. Thisprocedure blocked the on response to high frequency ipsilateral nervestimulation but not the increase in tonic activity in the EUS (FIG. 32b). These effects are consistent with activation of pelvic nerveafferents to evoke reflex responses in the EUS whilst interrupting nervetransmission past the distal ligature. Following ipsilateral nerveligation, repeated voiding continued in response to infusion of salineinto the bladder (FIG. 32d ). Moreover, stimulation of the pelvic nervewas still able to suppress imminent voids (FIG. 32d ).

Example Use Case #4—Inflammation

The systems, devices, techniques, protocols, and processes describedabove and throughout this document can be used in a variety of humanand/or animal applications. In one example use case, they can be used totreat patients with an inflammatory reflex associated with the spleenreleasing inflammatory cytokines by splenic macrophages into the bloodstream, which is often associated with conditions like depression andanxiety. Treatment of inflammatory reflexes can involve stimulating thevagus nerve to reduce the release of inflammatory cytokines (i.e.,trapped T cells originating in the GI tract) to cause a vagally mediatedreduction in lymphocyte release from the post-synaptic sites of vagusnerve innervation in the gastrointestinal tract. Vagus nerve stimulationcan be performed when particular conditions within the body are detectedthat indicate an inflammatory reflex is occurring or is about to occur,providing patients with warnings, such as on a mobile device (e.g.,smartphone, smart watch, other wearable device) and/or base station,stimulating various nerves and/or systems to reduce, stop, or preventthe inflammatory reflex a patient is experiencing, and/or othertherapeutic monitoring and/or treatment related to inflammationreflexes.

Example implementations for treating inflammation are described belowwith regard to FIGS. 33-34. Some or all of these features can be appliedto the treatment of other conditions, as described and/or withmodifications, and/or can be applied to the platform more generally.Additionally, some or all of the descriptions with regard to thetreatment of other conditions described throughout this document can beapplied inflammation reflex therapy.

Referring to FIG. 33, an example system 3300 is depicted in which animplantable system 3304 is configured for the treatment of inflammationreflex in a patient 3302. The example implantable system 3304 is similarto the implantable systems described above, and includes an implantablecontrol device 3306 (also referred to as a “bionode”) and one or moreseparate sensing and/or stimulating devices 3308 (e.g., implantablewireless electrodes), which can be wirelessly powered by the controldevice 3306 (no battery or other locally housed power source inimplantable devices 3308), can wirelessly transmit data to the controldevice 3306, and/or can be wirelessly controlled to dischargetherapeutic stimulation to one or more locations on the patient 3302.The system 3300 can provide a toolbox of implantable devices withaccompanying base station 3330 for wireless powering and a graphicaluser interface (GUI) (e.g., provided on a mobile device, like asmartphone or smartwatch) for wireless communication to and from thecontrol device 3306, which can be implanted in at one or more locationsin the patient's body, for example. The devices that are part of thesystem 3300 have the capacity for multi-channel neural recording,optical and electrical stimulation, wireless telemetry, wirelesspowering, and embedded algorithms for closed-loop feedback andstimulation.

The implantable electrodes 3308 in this example include one or morecytokine optrode 3320 (hybrid opto-electrode to measure real-timecytokine tracking) implanted at a location 3322 a that corresponds tothe patient's spleen. The control device 3306 is implanted at a location3322 b that corresponds to the patient's vagus nerve. The control device3306 includes an on-board compound nerve action potential (CNAP) devicethat can simultaneously record as a bioelectric input analog front end3316 and can provide nerve stimulation as a bioelectric stimulatoroutput 3319.

The implantable optical biosensors 3320 (i.e. optrodes) can providecontinuous monitoring of cytokines (e.g. TNF-alpha) in the spleen,blood, and brain by building cytokine sensitive micro-optrodes on animplantable optical bionode. These autonomous implantable sensors 3320can measure cytokine output in response to VNS stimulation to map andquantitatively define the neuro-inflammatory circuit and control loop asa dynamical system. The biosensors 3320 can be calibrated and validatedagainst blood and plasma cytokine levels measured by cytometric goldstandard methods, for example, using both experimental and referencesamples. The implantable optical biosensor 3320 measurements cancomplement the cytometric measurements, by providing a dynamic cytokinetime course and serve as the first existing prototype for therapeuticclosed-loop control of neuro-inflammation. Together these sets of outputdata can provide a more complete data set for defining the controlsystem 3300.

The electrodes 3320 can take various measurements at the locations 3322a, which can be wireless transmitted to the control device 3306 foranalysis. The electrodes 3320 can sense and transmit, for example,cytokine measurements from the patient's spleen to the control device3306, which can also receive the CNAP input from the on-boardbioelectric input analog front end 3316.

In addition to receiving and monitoring conditions related toinflammation in the patient 3302, determining particular therapeuticstimulation that should be provided to the patient 3302, and wirelesslydirecting one or more of the electrodes 3320 and/or the bioelectricstimulator output 3319 to deliver the determined therapy, the controldevice 3306 can include components to provide wireless data and power(3322) that permits the control device 3306 to wirelessly output data toa base station and/or to a mobile device (e.g., smartphone, smartwatch), and to be wirelessly powered and/or charged. This output datacan include a variety of different patient data, such as patient data, alog of conditions detected and therapies delivered, alerts as tocurrently detected conditions (e.g., oncoming inflammation, inflammationreflex currently detected), and/or other data. The control device 3306can transmit this data wirelessly. The control device 3306 can bepowered wirelessly (e.g., via RF signals) and can additionally include alocal power source (e.g., battery) that can be charge via the wirelesssignals and that can power the control device 3306 when the wirelesssignal is unavailable. The packaging of the control device 3306 can be,for example, a 3D print polymer.

The control device 3306 includes an analog front end 3310 that receiveswireless signals transmitted by the electrodes 3320. The analog frontend 3310 provide the received signals to the signal processing subsystemon the device 3306, which can include a microcontroller 3314 andfield-programmable gate array (FPGA). Signal processing can be performedon-board or off-board, and can involve using a closed-loop algorithm3318, which can be used to identify particular physiological conditionswithin the patient 3302 and can determine, based on the particulardetected conditions, whether to provide bioelectric stimulation at oneor more of the vagus nerve (location 3322 b). For example, theclosed-loop algorithm 3318 can be performed by the control device 3306,by a device external to the control device 3306 (e.g., mobile device,base station), or by a combination of the two. When a condition isdetected that warrants stimulation, the closed-loop algorithm 3318 candirect the bioelectric stimulator output unit 3319 to either directlyprovide the therapy or to cause one of the electrodes 3320 to deliverthe therapy. For example, the control device 3306 can include on-boardcomponents to delivery stimulation therapy (CNAP device 3319), and/orcan trigger one of more of the electrodes 3320 to deliver the therapy.

The closed-loop algorithm 3318 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 3302 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 3302. For example, the closed-loop algorithm3318 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 3302. After being initially calibrated, the closed-loopalgorithm 3318 can continue to learn and adapt over time by analyzingdata generated by the electrodes 3320, therapy provided to the patient3302, and the patient's response to the therapy.

A physiological pathway 3324 that is being monitored as part of thesystem 3300, which includes behavioral modifications (e.g., onset and/oralleviation of depression, anxiety, etc.), vagus nerve (including afunctional map and anatomical map of the vagus nerve to physiologicalresponses and structures), gut, T-lymphocyte release, lymphocytetrapping (spleen), and cytokine release. The closed-loop control that isbeing implemented by the closed-loop algorithm 3318 is directed towardmonitoring and providing therapy related to the physiological pathway3324, which includes receiving sensor data from electrode 3320 implantedat the spleen, processing those signals in combination with the CNAPsignals, and stimulating the vagus nerve to impact and minimize theinflammation reflex when, for example, the patient 102 is experiencingdepressions and/or anxiety as caused by a cytokine release. Cytokinemeasurement 3326 can be taken using the cytokine optrode 3320 and usedto determine whether the stimulation was sufficient to stop the cytokinerelease (which can occur in some patients experiencing behavioralchanges), and thereby stop/minimize the inflammation reflex. Theclosed-loop algorithm 3318 can repeatedly monitor the cytokine levelsand apply vagus nerve stimulation when appropriate until the patient'sinflammation reflex has stopped and/or dropped below a threshold level.The closed-loop algorithm 3318 can be automatically implemented withoutexplicit patient direction.

The system 3300 can deliver electrical stimulations to the patient 3302using appropriate stimulating frequency, waveforms, time delay fromdetection, stimulus current output, and other parameters to deliverneural therapy to allow for clamping the evoked cytokine response so asto modify the patient's behavior (e.g., alleviate feelings of depressionand anxiety). Such parameters can be patient-specific, and can bedeveloped through data collected during in-clinic/hospital monitoring ofseizure episodes and the patient response to various levels ofstimulation therapy.

A closed loop control can be used to implement the closed loop algorithm3318, which can determine therapeutic doses based on indirect measuresthat are likely to affect a patient's response to a given treatment. Forexample, the degree of neural activation in response to a given dose ofstimulus varies greatly from patient to patient (e.g., as a result ofgenetics, tissue/immune response to the implant, or environmentalfactors), and changes over time in individual patients. This responsevariability can be especially problematic when electrical nervestimulation is used to treat a biological dysfunction (i.e.,electroceuticals as an electrical correlate of pharmaceuticals).

Within safe limits, a physician does not care what the dose of therapyis, so much as the amount of evoked biomarker response. It follows thata better way of delivering therapy is to track and maintain a constantbiomarker response, allowing the strength of electrical stimulation tovary freely according to objective, quantifiable patient and diseasecharacteristics. This approach, implemented in the mathematical modelingunderlying the closed loop control algorithm (e.g., closed loopalgorithm 3318), provides advantages, including improved and moreconsistent patient therapy. Closed loop control is a self-optimizingpairing of custom software (described with regard to FIG. 34) andhardware (i.e. the system 3304) that adapts electrical stimulationparameters on the fly to the measured response of each nerve and neurontype stimulated. Through closed-loop biological feedback control, closedloop control maintains a constant dose of neural activation rather thanstimulation. Using closed loop control, a prescribed dose of neuralactivation, ranging from 0 to 100%, can be maintained in the samemanner, independently for each fiber type, across patients and withinthe same patient over time. In this way it serves as a toolautomatically identify relationships between the degree and pattern ofneural activation and therapeutic efficacy. Moreover, it allows for therapid if not immediate deployment of stimulus parameters that areoptimized for each patient, nerve and neuron type.

Referring to FIG. 34, an example system 3400 is depicted in which thecontrol device 3306 provides simultaneous stimulation and readings(e.g., using the CNAP device) on a nerve 3402 (e.g., vagus nerve) aspart of a closed loop control algorithm 3410, which can provideconstant-voltage stimulation.

The closed loop control 3410 program is loaded/modified (3412), itreceives and conditions nerve activation (3424) at the electrode 3404mounted to the nerve 3402 (3414). The closed loop control 3410 thendeconstructs stimulus-evoked compound nerve action potential (CNAP)responses (3416), recorded at a fixed distance from the stimulatingcathode, to estimate the level and type of nerve fiber activation, forexample. Conduction velocity is used to identify distinct nerve fibergroups (i.e., neuron populations), referred to as A (fast, myelinatedfibers), B (slow, myelinated fibers), or C (slow, unmyelinated fibers).When recording at a fixed, known distance from the stimulating cathode,the CNAP response waveform peaks can be separated in time due to thediffering conduction velocities of A, B and C fibers. The maximal CNAPresponse, otherwise referred to as maximal activation, is the CNAPresponse magnitude at which an increase in stimulus intensity does notproduce an increase in response. By individually derivingstimulus-response relationships for A, B and C fibers, the effect of anystimulus pulse on nerve activity is directly measurable. The resultingmodel (3418), known as a nerve activation profile, describes thesensitivity and dynamic range of each fiber type that can be identifiedin a CNAP. The closed loop control algorithm 3410 constructs it frommeasured data in under a minute, for example. The 3306 running theclosed loop control 3410 can further continuously update the activationprofile (3418) to improve its prediction accuracy over time and adapt tothe variety of factors that influence the efficacy of stimulation. Theupdated profile can then be used to make decisions regarding stimulationtherapy (3420) and, based on the decisions, to apply personalizedstimulus adjustments of the nerve 3402 by activating 3426 the electrodeattachment 3406.

Example Use Case #5—Alcoholism

In another example use case, the systems, devices, techniques,protocols, and processes described above and throughout this documentcan be used can be used to treat patients with alcoholism. Suchtreatments can include, for example, deep brain stimulation at targetedlocations to reduce alcohol intake, providing patients with warnings,such as on a mobile device (e.g., smartphone, smart watch, otherwearable device) and/or base station, and/or other therapeuticmonitoring (e.g. monitoring dopamine transmission) and/or treatmentrelated to chronic alcoholic intake.

Example implementations for treating alcoholism are described below withregard to FIG. 35. Some or all of these features can be applied to thetreatment of other conditions, as described and/or with modifications,and/or can be applied to the platform more generally. Additionally, someor all of the descriptions with regard to the treatment of otherconditions described throughout this document can be applied alcoholismtherapy.

Referring to FIG. 35, an example system 3500 is depicted in which animplantable system 3504 is configured for the treatment of alcoholism ina patient 3502. The example implantable system 3504 is similar to theimplantable systems described above, and includes an implantable controldevice 3506 (also referred to as a “bionode”) and one or more separatesensing and/or stimulating devices 3508 (e.g., implantable wirelesselectrodes), which can be wirelessly powered by the control device 3506(e.g. no battery or other locally housed power source in implantabledevices 3508), can wirelessly transmit data to the control device 3506,and/or can be wirelessly controlled to discharge therapeutic stimulationto one or more locations on the patient 3502.

The implantable electrodes 3508 in this example include one or moreelectrodes implanted at particular locations in the patient's body,including at the cortex. These electrodes 3520 can take variousmeasurements at the cortex and/or one or more of these locations, whichcan be wireless transmitted to the control device 3506 for analysis. Insome embodiments, the electrodes 3520 can sense and transmit, forexample, single neuron measurements, local field potential (LFP), andelectroencephalogram (EEG). The electrodes 3520 can also wirelesslydischarge therapeutic stimulation at the cortex and/or one or more ofthese locations when directed to do so by the control device 3506. Thisstimulations can include, for example, deep brain stimulation (DBS).

In addition to receiving and monitoring conditions in the patient 3502,determining particular therapeutic stimulation that should be providedto the patient 3502, and wirelessly directing one or more of theelectrodes 3508 to deliver the determined therapy, the control device3506 can include components to provide wireless data and power (3512)that permits the control device 3506 to wirelessly output data to a basestation and/or to a mobile device (e.g., smartphone, smart watch), andto be wirelessly powered and/or charged. This output data can include avariety of different patient data, such as patient data, a log ofconditions detected and therapies delivered, alerts as to currentlydetected conditions, and/or other data. The control device 3506 cantransmit this data wirelessly. The control device 3506 can be poweredwirelessly (e.g., via RF signals) and/or can additionally include alocal power source (e.g., battery) that can be charged via the wirelesssignals and that can power the control device 3506 when the wirelesssignal is unavailable.

The control device 3506 can receive wireless signals transmitted by theelectrodes 3508. For example, an analog front end can provide thereceived signals to the signal processing subsystem on the device 3506,which includes a microcontroller 3514. Signal processing can beperformed on-board or off-board, and can involve using a closed-loopalgorithm, which can be used to identify particular physiologicalconditions within the patient 3502 and can determine, based on theparticular detected conditions, whether to provide bioelectricstimulation. For example, a closed-loop algorithm can be performed bythe control device 3506, by a device external to the control device 3506(e.g., mobile device, base station), or by a combination of the two.When a condition is detected that warrants stimulation, the closed-loopalgorithm can direct the bioelectric stimulator output unit to eitherdirectly provide the therapy or to cause one of the electrodes 3508 todeliver the therapy. For example, the control device 3506 can includeon-board components to delivery stimulation therapy, and/or can triggerone of more of the electrodes 3520 to deliver the therapy.

A physiological pathway 3524 can be monitored as part of the system3500. In an example embodiment, the patient's cortex is monitored,including the patient's response to deep brain stimulation delivered bythe electrode 3508. Closed-loop control may be implemented to monitorand provide therapy related to the physiological pathway 3524, and mayinclude receiving sensor data from electrode 3508 implanted at thecortex, processing the data, and stimulating the cortex to impact neuralactivity in the cortex (or in the nucleus accumbens shell, for example).The closed-loop control may result in stimulus delivered by electrode3508 based on detected patient conditions. Alternatively or in addition,stimulus may be delivered at predetermined intervals or according to apredetermined pattern.

In an example embodiment, system 3500 is configured to regulate themesocorticolimbic system. One or more electrodes may be positioned todeliver deep brain stimulation of the nucleus accumbens shell (AcbSh).The AcbSh is a neuroanatomical substrate that can have reinforcingeffects of alcohol. Reversible inactivation of the AcbSh has been foundto regulate chronic alcohol intake. Alternatively or in addition, one ormore electrodes 3508 may be positioned to monitor and/or deliverstimulus proximate throughout the midbrain dopaminergic system, such asthe ventral tegmental area, nucleus accumbens, olfactory tubercle,frontal cortex, and amygdala. In an example embodiment, unilateral deepbrain stimulation is delivered (e.g. only to the left AcbSh).Alternatively or in additional, bilateral deep brain stimulation may bedelivered (e.g. to both the left and right AcbSh). Deep brainstimulation delivered to patient 3502 by system 3500 may at leastpartially normalize an otherwise deficient dopaminergic system throughalterations in dopamine and dopamine related enzyme levels.Alternatively or in addition, system 3500 may alter neurophysiologicalinteractions, such as abnormal neuronal discharge and excessivesynchrony that may otherwise occur in and/or between cortical andsubcortical sites (e.g. in diseases related to dopamine depletion).

Electrodes 3508 are configured to deliver a stimulus that provides an atleast partial inactivation of a target brain location, such as that ofvarious subjects (e.g., animals, like rats, humans). In an exampleembodiment, the stimulus is delivered as a biphasic, anode-leading,rectangular pulse with no interphasic delay, a pulse frequency ofbetween about 50 Hz and 500 Hz (e.g. about 150 Hz), a pulse widthbetween 1 μsec and 1000 μsec (e.g. about 100 μsec), and currentintensities between 25 μA and 1000 μA (e.g. 100 μA (n=3) or 200 μA(n=4)).

Deep brain stimulation may be delivered by system 3500 according to apredetermined schedule. For example, electrodes 3508 may be instructedto deliver stimulation during a predetermined period (e.g. apredetermined period each hour, each day, each week, etc.). Deep brainstimulation may be delivered during a one-hour period each day for aperiod of days.

Example Use Case #6—Parkinson's

Referring now to FIG. 36, the systems, devices, techniques, protocols,and processes described above and throughout this document can be usedfor preclinical trials of subjects with Parkinson's disease. Suchpreclinical tirals can include, for example, stimulating the targetareas of the brain (e.g. cortical and subcortical structures) ofsubjects with Parkinson's.

Example implementations for preclinical trials related to Parkinson'sdisease are described herein with regard to FIG. 36. Some or all ofthese features can be applied to the treatment of other conditions, asdescribed and/or with modifications, and/or can be applied to theplatform more generally. Additionally, some or all of the descriptionswith regard to the treatment of other conditions described throughoutthis document can be applied to Parkinson's disease studies.

Referring to FIG. 36, an example system 3600 is depicted in which animplantable system 3604 is configured for preclinical trials related tosubjects with Parkinson's disease in a patient 3602. The exampleimplantable system 3604 is similar to the implantable systems describedabove, and includes an implantable control device 3606 (also referred toas a “bionode”) and one or more separate sensing and/or stimulatingdevices 3608 (e.g., implantable wireless electrodes), which can bewirelessly powered by the control device 3606 (e.g., no battery or otherlocally housed power source in implantable devices 3608), can wirelesslytransmit data to the control device 3606, and/or can be wirelesslycontrolled to discharge therapeutic stimulation to one or more locationson the patient 3602.

The implantable electrodes 3608 in this example include one or moreelectrodes 3620 implanted at particular locations 922 a in the patient'sbody, including at the cortex 922 a. These electrodes 3620 can takevarious measurements at one or more of these locations, which can bewireless transmitted to the control device 3606 for analysis. Theseelectrodes 3620 can sense and transmit, for example, single neuronmeasurements, local field potential (LFP), and electroencephalogram(EEG). These electrodes 3620 can also wirelessly discharge therapeuticstimulation at one or more of these locations when directed to do so bythe control device 3606. This stimulation can include, for example, deepbrain stimulation (DBS).

In addition to receiving and monitoring conditions related toParkinson's disease in the patient 3602, determining particulartherapeutic stimulation that should be provided to the patient 3602, andwirelessly directing one or more of the electrodes 3620 to deliver thedetermined therapy, the control device 3606 can include components toprovide wireless data and power (3622) that permits the control device3606 to wirelessly output data to a base station and/or to a mobiledevice (e.g., smartphone, smart watch), and to be wirelessly poweredand/or charged. This output data can include a variety of differentpatient data, such as patient data, a log of conditions detected andtherapies delivered, alerts as to currently detected conditions (e.g.,oncoming seizure, seizure currently detected), and/or other data. Thecontrol device 3606 can transmit this data wirelessly. The controldevice 3606 can be powered wirelessly (e.g., via RF signals) and canadditionally include a local power source (e.g., battery) that can becharge via the wireless signals and that can power the control device3606 when the wireless signal is unavailable.

In some embodiments, the implantable system 3604 includes featuressimilar to the implantable system 3604 described above. The controldevice 3606 includes an analog front end 3610 that receives wirelesssignals transmitted by the electrodes 3620. The analog front end 3610provide the received signals to the signal processing subsystem on thedevice 3606, which includes a microcontroller 3614 andfield-programmable gate array (FPGA) 3616, which is an integratedcircuit designed to be configured after manufacturing.

Signal processing can be performed on-board or off-board, and caninvolve using a closed-loop algorithm 3618, which can be used toidentify particular physiological conditions within the patient 3602 andcan determine, based on the particular detected conditions, whether toprovide bioelectric stimulation at one or more locations, such aslocation 3622. For example, the closed-loop algorithm 3618 can beperformed by the control device 3606, by a device external to thecontrol device 3606 (e.g., mobile device, base station), or by acombination of the two. When a condition is detected that warrantsstimulation (e.g. based on cortical activity), the closed-loop algorithm3618 can direct the bioelectric stimulator output unit 3618 to eitherdirectly provide the therapy or to cause one of the electrodes 920 todeliver the therapy. For example, the control device 3606 can includeon-board components to delivery stimulation therapy, and/or can triggerone of more of the electrodes 3620 to deliver the therapy.Implementation using an embedded FPGA-based algorithm can reducetelemetry burden and allow a longer battery life.

The closed-loop algorithm 3618 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 3602 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 3602. For example, the closed-loop algorithm3618 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 3602. After being initially calibrated, the closed-loopalgorithm 3618 can continue to learn and adapt over time by analyzingdata generated by the electrodes 3620, therapy provided to the patient3602, and the patient's response to the therapy.

System 3600 may monitor one or more physiological pathways 3624, whichincludes monitoring cortical activity of patient 3602. The closed-loopcontrol implemented by the closed-loop algorithm 3618 is directed towardmonitoring and providing therapy related to the physiological pathway3624, which includes receiving sensor data from electrodes 3620implanted at the cortex, for example.

In an example embodiment, system 3600 is configured to regulateexcessive beta-band oscillation synchrony in the basal ganglia and otherstructures. For example, electrodes 3620 are configured to deliverystimulation to subcortical structures, including structures within thebasal ganglia-thalmocortical loop, according to the closed-loop control3618. One or more electrodes 3620 may be configured to stimulate thesubthalamic nucleaus.

The closed-loop control 3618 may use cortical neural activity, at leastin part, for feedback. Cortical neural activity has been found to bestable and relatively easy to measure, and can provide an accurateindicator of basal ganglia activity. For example, cortical activity maybe measured by EEG or subcranial electrodes, and stimulation deliveredby electrodes 3620 based on the detected cortical activity.

The stimulus parameters may be configured to improve treatment efficacywhile reducing power requirements and ensuring patient safety. In someexample embodiments, the waveform of the stimulation delivered byelectrode 3620 may have a relatively small amplitude while targeted toreduce the pathological activity which results in primary symptoms. Sucha waveform may provide enhanced suppression of symptoms with reducedsized affects, while also reducing power consumption. Similarly,high-frequency pulse shaping can increase fiber recruitment, reducespower consumption, and enhances selectivity.

Example Use Case #7—Gastric Disorders

Referring now to FIG. 37, the systems, devices, techniques, protocols,and processes described above and throughout this document can be usedto treat gastric disorders. Such treatments can include, for example,stimulating the vagus nerve when particular conditions within the bodyare detected, providing patients with warnings, such as on a mobiledevice (e.g., smartphone, smart watch, other wearable device) and/orbase station, stimulating various nerves and/or systems to ameliorategastric conditions, and/or other therapeutic monitoring and/or treatmentrelated to the stomach.

An example implementation for treating gastric disorders are describedbelow with regard to FIG. 37. Some or all of these features can beapplied to the treatment of other conditions, as described and/or withmodifications, and/or can be applied to the platform more generally.Additionally, some or all of the descriptions with regard to thetreatment of other conditions described throughout this document can beapplied to gastric therapy.

Referring to FIG. 37, an example system 3700 is depicted in which animplantable system 3704 is configured for the treatment of gastricdisorders in a patient 3702. The example implantable system 3704 issimilar to the implantable systems described above, and includes animplantable control device 3706 (also referred to as a “bionode”) andone or more separate sensing and/or stimulating devices 3708 (e.g.,hormone optrodes, implantable wireless electrodes), which can bewirelessly powered by the control device 3706 (e.g., no battery or otherlocally housed power source in implantable devices 3708), can wirelesslytransmit data to the control device 3706, and/or can be wirelesslycontrolled to discharge therapeutic stimulation to one or more locationson the patient 3702. The system 3700 can provide a toolbox ofimplantable devices with accompanying base station 3730 for wirelesspowering and a graphical user interface (GUI) (e.g., provided on amobile device, like a smartphone or smartwatch) for wirelesscommunication to and from the control device 3706, which can beimplanted in the vagus-stomach neural circuitry, for example. Thedevices that are part of the system 3700 have the capacity formulti-channel neural recording, optical and electrical stimulation,wireless telemetry, wireless powering, and embedded algorithms forclosed-loop feedback and stimulation. FIG. 37 depicts a schematic viewof an example implementation of the system 3700, with examples of thebase station 3730, the implantable system 3704, the control device 3706,the implantable sensing and stimulating devices 3708, and nervous tissue3722, such as the vagus nerve to which therapy is applied and/ormeasurements are taken.

The implantable electrodes 3708 in this example include one or moreelectrodes 3720 implanted at particular locations in the patient's body,including at one or more locations of the vagus nerve 3722 a, and/or gut3722 b. These electrodes 3720 can take various measurements at one ormore of these locations 3722 a, 3722 b, which can be wirelesstransmitted to the control device 3706 for analysis. These electrodes3720 may include one or more hormone optrodes that can sense andtransmit, for example, levels of ghrelin, PYY, somatostatin, gastrin,nesfatin, leptin and 5-HT (e.g. in the stomach), and/or CCK, secretin,5-HT, GIP, GLP-1, PYY and neurotensin (e.g. in the duodenum).Alternatively or in addition, various electrodes 3720 can be includedthat sense and transmit, for example, single neuron measurements, localfield potential (LFP), and electroencephalogram (EEG). These electrodes3720 can also wirelessly discharge therapeutic stimulation at one ormore of these locations 3722 a, 3722 b when directed to do so by thecontrol device 3706.

In addition to receiving and monitoring conditions related to gastricdisease in the patient 3702, determining particular therapeuticstimulation that should be provided to the patient 3702, and wirelesslydirecting one or more of the electrodes 3720 to deliver the determinedtherapy, the control device 3706 can include components to providewireless data and power that permits the control device 3706 towirelessly output data to a base station and/or to a mobile device(e.g., smartphone, smart watch), and to be wirelessly powered and/orcharged. This output data can include a variety of different patientdata, such as patient data, a log of conditions detected and therapiesdelivered, alerts as to currently detected conditions (e.g., related toappetite), and/or other data. The control device 3706 can transmit thisdata wirelessly. The control device 3706 can be powered wirelessly(e.g., via RF signals) and can additionally include a local power source(e.g., battery) that can be charge via the wireless signals and that canpower the control device 3706 when the wireless signal is unavailable.The packaging of the control device 3706 can be, for example, glass.

The control device 3706 include an optical analog front end 3710 thatreceives wireless signals transmitted by the electrodes 3720. Theoptical analog front end 3710 provide the received signals to the signalprocessing subsystem on the device 3706, which includes amicrocontroller 3714 and field-programmable gate array (FPGA) 3716,which is an integrated circuit designed to be configured aftermanufacturing. Signal processing can be performed on-board or off-board,and can involve using a closed-loop algorithm 3718, which can be used toidentify particular physiological conditions within the patient 3702 andcan determine, based on the particular detected conditions, whether toprovide bioelectric stimulation at one or more of the locations 3722 a,3722 b. For example, the closed-loop algorithm 3718 can be performed bythe control device 3706, by a device external to the control device 3706(e.g., mobile device, base station), or by a combination of the two.When a condition is detected that warrants stimulation, the closed-loopalgorithm 3718 can direct the bioelectric stimulator output unit 3719 toeither directly provide the therapy or to cause one of the electrodes3720 to deliver the therapy. For example, the control device 3706 caninclude on-board components to delivery stimulation therapy, and/or cantrigger one of more of the electrodes 3720 to deliver the therapy.

The closed-loop algorithm 3718 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 3702 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 3702. For example, the closed-loop algorithm3718 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 3702. After being initially calibrated, the closed-loopalgorithm 3718 can continue to learn and adapt over time by analyzingdata generated by the electrodes 3720, therapy provided to the patient3702, and the patient's response to the therapy.

In an example embodiment, a physiological pathway 3724 monitored as partof the system 3700 can include the vagus nerve (e.g., branches of thevagus nerve associated with the stomach, its sphincters (loweresophageal sphincter; pylorus), and neighboring segments of the GI tract(distal esophagus; proximal duodenum)). The closed-loop controlimplemented by the closed-loop algorithm 3718 is directed towardmonitoring and providing therapy related to the physiological pathway3724, which includes receiving sensor data from electrodes 3720 andstimulating the vagus to engage vago-vagal reflexes. In an exampleembodiment, the closed-loop control includes monitoring of compoundaction potentials, smooth muscle activity, coordinated gastric emptying,reflux, hormone release, CNS activations, and control of meals ingested.

Hormone measurement 3726 can be taken using the electrodes 3720 (e.g.,hormone optrodes) and used to analysis the efficacy of the stimulation.The closed-loop algorithm 3718 can repeatedly monitor hormone levels andapply vagus nerve stimulation when appropriate until the desired gastricsystem response is achieved. The closed-loop algorithm 3718 can beautomatically implemented without explicit patient direction,continuously monitoring and adjusting delivery of stimulation to thevagus nerve.

The system 3700 can deliver electrical stimulations to the patient 3702using appropriate stimulating frequency, waveforms, time delay fromdetection, stimulus current output, and other parameters to deliverneural therapy. Such parameters can be patient-specific, and can bedeveloped through data collected during in-clinic/hospital monitoring ofgastric response to various levels of stimulation therapy. At abehavioral level, wireless closed-loop implantable devices included inthe system 3700 can use a range of stimulation parameters to allow formultifactorial modifications to address these complex problems.

A reliable gastric response feedback algorithm facilitates successfulclosed-loop therapy of system 3700. Similar to other use cases describedherein, the device 3706 can use a digital ASIC algorithm that isultralow power, reduces the device profile, and is specifically designedfor specialized gastric disease applications. Through the use of a lowpower microcontroller (e.g., microcontroller 1514), custom algorithmscan be implemented. For instance, additional and/or alternative controlalgorithms can be implemented for other conditions, such as forpsychiatric therapy that can observe correlations between a wide rangeof longitudinal behaviors, gamma and theta oscillations, and stimulationparadigms to increase or decrease activity of certain neural populationsin response to the oscillations (e.g. related to appetite or otherparameters of the gastric system).

In various exemplary embodiments, biomodulation protocols of system 3700are configured to bioelectronically ameliorate and monitor gastricdisorders such as gastroparesis (e.g., modulating nausea and vomiting inpatients receiving gastric stimulation for diabetic gastroparesis),obesity, tachygastria, motility problems, reflux disorders such asgastroesophageal reflux disease (GERD) disease, and eating disorders.The stomach has been found to be appropriate and accessible forbiomodulation delivered by system 3700 (e.g., via electrodes 3720)because the vagus nerve provides multiple candidate sites for electrodeaccess. Electrodes 3720 may be located at one or moreelectrode-accessible vagal branches that innervate regions of thestomach, for example.

System 3700 may be configured for focal biomodulation of afferentconcentrations (e.g., without stimulation of entire branches or trunksof the vagus. Increasing or decreasing the activity of afferents (e.g.,putative stretch receptors of the vagal afferent intramuscular arrays(IMAs)) have been found to be a more natural mode of engaging vago-vagalreflexes. Stimulation of afferent concentrations may generate activitythat engages the more programmed elements of the reflex arcs.

In an example embodiment, electrodes 3720 are configured to monitorcompound nerve action potential (CNAP) from vagus or electrogastrogram(EGG) from the antrum and other compartments of the stomach. Themeasured signals are buffered, filtered, and differentially amplifiedand converted to a single-ended output in an instrumentation amplifier.A band-pass filter removes physiological and extraneous (e.g.,high-frequency monitor or dc drift) noise above 5 kHz or below 1 Hz,while passing the signals of interest between those cutoffs. A secondamplifier stage can have a selectable gain of 100-1,000 (e.g.,programmable) to place the expected input amplitude range in the 0-1 Vdynamic range of the analog-to-digital converter. Simulation from thebioelectric stimulator output unit 3719 is delivered constant currentwith 1 μA resolution, 12 V headroom, and up to 1 mA peak current, forexample.

During operation of system 3700, gastric hormones may be opticallysensed by hormone optrodes of electrodes 3720. For example, an examplehormone optrode may be a micro-optrode grown by photopolymerization of apolyethylene glycol (PEG) diacrylate and silica composite material,which has been optimized for biomolecule based biosensing. The PEGhydrogel maintains sensor biomolecule stability and controls thematerial porosity for good temporal response. The acrylate provides thelight controlled growth to modify the tip geometry for the implant site.The porous silica provides stability, structural integrity, and goodadhesion to the optical fiber. The micro-optrode may be grown on the tipof an optical fiber (e.g. a 100 um optical fiber) that is connected tothe internal microoptics and microelectronics (e.g., that communicatewith components of implantable system 3704).

Example Use Case #8—Addiction

The systems, devices, techniques, protocols, and processes describedabove and throughout this document can be used in a variety of humanand/or animal applications. In one example use case, they can be used totreat patients with addiction. Addiction is a chronic disease of brainreward, motivation, memory and related circuitry. Dysfunction in thesecircuits leads to characteristic biological, psychological, social andspiritual manifestations. This is reflected in an individualpathologically pursuing reward and/or relief by substance use and otherbehaviors. Addiction is characterized by inability to consistentlyabstain, impairment in behavioral control, craving, diminishedrecognition of significant problems with one's behaviors andinterpersonal relationships, and a dysfunctional emotional response.Like other chronic diseases, addiction often involves cycles of relapseand remission. Without treatment or engagement in recovery activities,addiction is progressive and can result in disability or prematuredeath. Treatments to treat patients can include, for example,stimulating the vagus nerve when particular conditions within the bodyare detected that indicate a possible neurological condition associatedwith addiction, providing patients with controls and/or indications,such as on a mobile device (e.g., smartphone, smart watch, otherwearable device) and/or base station, stimulating various nerves and/orsystems to reduce the incident of changes in the function of multiplebrain circuits that control pleasures/reward, stress, decision-making,impulse control, learning and memory, and other functions, and/or othertherapeutic monitoring and/or treatment related to addiction.

Example implementations for therapeutic stimulation of addiction aredescribed below with regard to FIG. 38. Some or all of these featurescan be applied to the treatment of other conditions, as described and/orwith modifications, and/or can be applied to the platform moregenerally. Additionally, some or all of the descriptions with regard tothe treatment of other conditions described throughout this document canbe applied to addiction therapy.

Referring to FIG. 38, an example system 3800 is depicted in which animplantable system 3804 is configured for the treatment of addiction ina patient 3802. The example implantable system 3804 is similar to theimplantable systems described above, and includes an implantable controldevice 3806 (also referred to as a “bionode”) and one or more separatesensing and/or stimulating devices 3808 (e.g., implantable wirelesselectrodes), which can be wirelessly powered by the control device 3806(no battery or other locally housed power source in implantable devices3808), can wirelessly transmit data to the control device 3806, and/orcan be wirelessly controlled to discharge therapeutic stimulation to oneor more locations on the patient 3802. The system 3800 can provide atoolbox of implantable devices with accompanying base station 3830 forwireless powering and a graphical user interface (GUI) (e.g., providedon a mobile device, like a smartphone or smartwatch) for wirelesscommunication to and from the control device 3806.

The implantable electrodes 3808 in this example include one or moreelectrodes 3820 implanted at particular locations 3822 a-e in thepatient's body, including at the cortex 3822 a, the brainstem 3822 b,the vagus nerve 3822 c, the phrenic nerves 3822 d,diaphragm/intercostals 3822 e and/or other locations. For example, theelectrodes 3820 can be implanted in the brainstem 3822 b (e.g.,hippocampus, pre-Botzinger, nucleus ambiguus, nucleus tractussolitarius, and rostral and caudal ventral-lateral medulla (VLM)). Also,the electrodes 3829 can be implanted in various locations associatedwith the sympathetic nervous system (e.g., vagus, phrenic) whichactivates what is often termed the fight or flight response, and isoften associated with addiction. As an example, the electrodes 3829 candetect to local field potential and single and multiunit activity forevidence of excitation of the sympathetic nervous system, which may beindicative of addiction. These electrodes 3820 can take variousmeasurements at one or more of these locations 3822 a-e, which can bewired and/or wireless transmitted to the control device 3806 foranalysis. These electrodes 3820 can sense and transmit, for example,electric physiological conditions including single neuron measurements,LFP, EEG, electrocardiogram (ECG), and electromyogram (EMG). Theseelectrodes 3820 can also wirelessly discharge therapeutic stimulation atone or more of these locations 3822 a-e when directed to do so by thecontrol device 3806. This stimulation can include, for example, deepbrain stimulation (DBS) and/or nerve stimulation.

In addition to measuring electric physiological conditions using theelectrodes 3820, the implant system 3806 can use one or more sensors3816 to measure mechanical and/or chemical conditions within the patient3802. For example, the sensors 3816 can measure and provide data onmechanical physiological conditions including respiratory conditions(e.g., rate of respiration) and patient temperature. The sensors 3816can also measure and transmit chemical conditions including aptamer inthe patient's body. The sensors 3816 can be, for example, transducers.Such sensors 3816 can be either directly or indirectly (via leads)connected to particular physiological structures in the patient's body,such as ECG leads on the chest wall; EMG leads to diaphragm or othermuscle; and/or thermocouple implanted in the nasal passage.

In addition to receiving and monitoring conditions related to addictionin the patient 3802, determining particular therapeutic stimulation thatshould be provided to the patient 3802, and wirelessly directing one ormore of the electrodes 3820 to deliver the determined therapy, thecontrol device 3806 can include components to provide wireless data andpower (3812) that permits the control device 3806 to wirelessly outputdata to a base station and/or to a mobile device (e.g., smartphone,smart watch), and to be wirelessly powered and/or charged. This outputdata can include a variety of different patient data, such as patientdata, a log of conditions detected and therapies delivered, alerts as tocurrently detected conditions (e.g., sympathetic), and/or other data.The control device 3806 can transmit this data wirelessly. The controldevice 3806 can be powered wirelessly (e.g., via RF signals) and canadditionally include a local power source (e.g., battery) that can becharge via the wireless signals and that can power the control device3806 when the wireless signal is unavailable. The packaging of thecontrol device 3806 can be, for example, glass.

The control device 3806 includes an analog front end 3810 that receiveswireless signals transmitted by the electrodes 3820. The analog frontend 3810 provide the received signals to the signal processing subsystemon the device 3806, which includes a microcontroller 3814 and a FPGA.Signal processing can be performed on-board or off-board, and caninvolve using a closed-loop algorithm 3818, which can be used toidentify particular physiological conditions within the patient 3802 andcan determine, based on the particular detected conditions, whether toprovide bioelectric stimulation at one or more of the locations 3822a-e. For example, the closed-loop algorithm 3818 can be performed by thecontrol device 3806, by a device external to the control device 3806(e.g., mobile device, base station), or by a combination of the two.When a condition is detected that warrants stimulation, the closed-loopalgorithm 3818 can direct the bioelectric stimulator output unit 3818 toeither directly provide the therapy or to cause one of the electrodes3320 to deliver the therapy. For example, the control device 3806 caninclude on-board components to delivery stimulation therapy, and/or cantrigger one of more of the electrodes 3820 to deliver the therapy.

The closed-loop algorithm 3818 can use any of a variety of appropriatetechniques to learn the particular physiology of the patient 3802 andthe patient's particular response to therapy, and can use thatinformation to determine when, how, and under what conditions to providetherapy for the patient 3802. For example, the closed-loop algorithm3818 can be initially calibrated for the patient by a physician or othertrained technician in a clinical setting, which can involve providingvarious stimulations and recording the physiological response of thepatient 3802. After being initially calibrated, the closed-loopalgorithm 3818 can continue to learn and adapt over time by analyzingdata generated by the electrodes 3820, therapy provided to the patient3802, and the patient's response to the therapy.

A physiological pathway 3824 that is being monitored as part of thesystem 3800, which includes the patient's cortex, brainstem, vagusnerve, phrenic nerve, and diaphragm/intercostals. The closed-loopcontrol that is being implemented by the closed-loop algorithm 3818 isdirected toward monitoring and providing therapy related to thephysiological pathway 3824, which includes receiving sensor data fromelectrodes 3320 implanted at the cortex and brainstem and the electrodes3816 positioned to measure respiratory and temperature information,processing those signals, and stimulating the vagus nerve. Measurementscan be taken by the electrodes 3816 and 3820, and can be used todetermine whether the stimulation was sufficient to mitigate thedetected condition (which can occur in some patients experiencingseizures), and thereby stop/minimize the condition that may indicate theonset of and overdose. The closed-loop algorithm 3818 can repeatedlymonitor patient data and apply vagus nerve stimulation when appropriateuntil the patient's additive condition (e.g., overdose) has stoppedand/or dropped below a threshold level. The closed-loop algorithm 3818can be automatically implemented without explicit patient direction.

The closed-loop VNS therapy provided by the system 3800 in response to,for example, alterations in cardiac or respiratory rate has thepotential to reduce the incidence of conditions related to addiction.Other factors and alterations in other factors can additionally and/oralternatively be used to identify the onset of potentially harmful orfatal addictive conditions and via stimulation. For instance, increasesin certain levels of chemicals, or neurotransmitters, in the brain, canbe indicative of an overdose situation, which results in levels that canharm the central nervous system (the brain and spinal cord). The system3800 can be configured to prevent damage to nerves from the brain stemcaused by the overdose, which untreated can cause opthalmoplegia(weakness of the muscle that controls the eyes), induce delirium orseizures.

The system 3800 take a variety of patient factors into account as partof the closed-loop algorithm, including biological factors,environmental stimulants, stress, diet, and overall health andcorrelations and their consequences. Moreover, aspects related to SUDEPcan be utilized in application involving addiction. Thus, the system3800 can provide a platform to identify unit and local field potentialsassociated with seizures, overdose, and/or addiction related changes inheart rate, respiration, arrhythmias and apneas. Temporal relationshipsbetween unit activity and postictal cardio-respiratory changes will shedlight on mechanism. E.g., tachycardia continuing long after cessation ofpostictal changes in neuronal activity in cardiac centers (notably VLM)would implicate an endocrine component. To be able to detect anyseizure-like activity propagating into the brainstem, recordings will bemade wider band than is conventional for unit recordings. Off-linefiltering can be implemented to help isolate unit activity.

For the example use cases #1-8 described above, absent an explicitdiscussion on the location other the implantable control device, theimplantable control device can be inserted in any of a variety oflocations within the patient's body, such as in or near the point ofstimulation, in or near the point of monitoring, in one or more cavitieswithin the body, and/or other appropriate locations for transmitting andreceiving wireless signals.

Pressure Monitoring Chip

The pressure monitoring chips, devices, systems, assemblies, andtechniques described below can be used in combination with the systems,devices, chips, assemblies, and techniques described above.

Biological pressure measurement is a common diagnostic procedureconducted by physicians. For example, a blood pressure measurement isperformed routinely in the physician's office along with other vitalsigns. In addition to the diseases diagnosis, biological pressuremonitoring enables a necessary framework required to study theprogression of complex diseases and disorders. Urinary incontinence (UI)is an example of such progressive diseases. The loss of bladdersensation or control due to a high bladder pressure imposes serioushealth risks to the patients suffering from UI.

Since the bladder pressure has diurnal variations, continuous monitoringis highly desirable. However, the currently available methods are notadequate to provide continuous biological pressure monitoring. Forbladder pressure measurement, a catheter-based pressure sensing deviceis commonly utilized. In this technique catheter tubes are directlyinserted into the bladder through the urethra to measure the bladderpressure. The catheter-based procedure is not feasible for long-termbladder pressure monitoring and presents a urinary tract infection riskto the patients. Additionally, catheter disturbances produce errors inthe pressure measurements.

Recent advances in low power integrated circuit (IC) design, minusculebiosensors, and wireless power transfer (WPT) have laid the foundationfor fully wireless, miniaturized implantable microsystems that can beutilized in many biomedical applications including pressure sensing. Anunprecedented level of miniaturization is possible with suchmicrosystems which make them an ideal candidate for biological pressuresensing applications. FIG. 39A shows the target implant location forbladder pressure monitor systems. FIG. 39B is a conceptual diagram of amicrosystem implant that comprises a pressure sensor, a readout IC, apowering coil and an antenna. The use of a pressure sensor for bladdermay be employed with any mammalian patient, including humans and animals(e.g. rodents).

The design of uninterrupted pressure sensing monitors presents a numberof design challenges, with size constraint and power consumption beingthe most important ones. As depicted in FIG. 39, due to the smallimplant site, the diameter and thickness of the receive coil for energyharvesting should preferably not exceed more than 2.6 mm and 100 μm,respectively. This area restriction limits the energy efficiency of theWPT and thus the instantaneous power consumption of the chip. The sizeconstraint for the implant also limits the combined dimensions of thepressure sensor and readout IC to 750 μm×750 μm×300 μm. Table 4.1illustrates the size specifications for pressure sensing microsystems.

Specifications for Pressure Monitoring Microsystem

Parameters Specifications ASIC dimensions <750 μm × 750 μm × 250 μmSensor dimensions <700 μm × 500 μm × 50 μm Telemetry antenna diameter<2.4 mm Powering coil size <2.6 mm; <100 μm thick ASIC peak powerconsumption <500 μW

State-of-the-art commercial capacitive pressure sensors (E1.3N, microFABBremen) are often employed in pressure sensing applications in humans,however, it cannot be used for animal studies due to its large size. Apush forward in piezoresistive pressure sensor fabrication technologyyields micro-scale sensors (700 μm×100 μm×50 μm) and thus make themideal candidates for this application. Apart from its smaller size, thepiezoresistive pressure sensor also offers better linearity thancapacitive sensors.

This disclosure presents a sub-cubic millimeter (sub-mm3) sizedcontinuous pressure monitoring microsystem that includes apiezoresistive differential pressure sensor, a fully wireless CMOSread-out ASIC, a loop antenna for data transmission, and a receiverpowering coil. The readout ASIC is highly integrated and senses thechange in differential resistance with applied pressure and provides aresistance-to-digital (R-D) conversion. The chip also includes a 2.45GHz ISM band active transmitter (TX) to wirelessly transmit the rawsensing data. The system is batteryless thereby increasing the life spanof the implant and is wirelessly powered by exciting a cavity resonatorat 340 MHz.

The main goal for the system is to provide all the necessaryfunctionality to the implant by designing a highly integratedsystem-on-chip (SoC), without using any external components, in thegiven size limit. Having features such as, on-chip first ordercalibration, data processing, active transmission and signalconditioning remove the need for a constant nearby external device toperform these tasks, which is essential in a scenario where theexperiments are done on a freely moving animal. A simple base station,such as a smartphone, kept a few tens of centimeters away, is all weneed to demodulate and display the pressure data in real time.

FIG. 40 shows the block diagram of a pressure sensing SoC that comprisesfour major blocks: energy harvesting (EH) and power management,resistance-to-frequency converter (R-F) front-end circuit, a digitalcore that finally provides a resistance-to-digital (R-D) conversion, anda 2.45 GHz ISM band TX. Also shown in the figure is a three-terminaldifferential piezoresistive pressure sensor, consisting of two resistiveelements R_(S1) and R_(S2), which senses the applied pressure P byincreasing the resistance of R_(S1) and decreasing the resistance ofR_(S2) by the same amount ΔRS (for R_(S2)>R_(S1)). The change indifferential resistance R_(DIFF) is given by:

R _(DIFF)=[R _(S2) −ΔR _(S)]−[R _(S1) +ΔR _(S)]

R _(DIFF)=(R _(S2) −R _(S1))−2ΔR _(S);(R _(S2) >R _(S1))

where, 2ΔRS is the change in the differential sense resistance with theapplied pressure P. The resistance of both the elements increases withthe temperature, thereby canceling out the temperature variation in adifferential measurement. The R-F front-end circuit measures the change2ΔRS and hence the applied pressure.

For WPT for rodents, 340 MHz RF energy is utilized to excite theresonance cavity. The use of a high value of frequency allows theimplant to harvest the energy with a very small, two-turn receive coil(100 μm thickness, and 2.6 mm diameter) and the on-chip adaptivematching network. The EH section of the SoC utilizes two capacitors forthe matching network, as can be seen in the FIG. 41. The drop-in powertransfer efficiency (PTE) due to the coil misalignment and other factorsis addressed by an efficiency tracking loop that maximizes PTE undervarious operating conditions by automatically tuning the capacitor bankin the matching network. In addition, a sub-1V bandgap reference (BGR)circuit is designed to provide the pseudo-differential reference andcommon mode voltages for the R-F front-end circuit. The BGR alsogenerates bias currents for the entire chip. Two on-chip n+ diffusionbase resistances (RB1 and RB2) were implemented with the values close tothe sensor resistances for calibration purposes.

A binary-counter based digital core logic provides the frequency todigital conversion and packetizes the data for wireless transmission.Finally, the data packets are transmitted by an On-Off-Key (OOK)modulated ISM band TX at 2.45 GHz. The TX consists of a voltagecontrolled power oscillator (VCPO) utilizing a LC resonant circuit togenerate its carrier frequency in the 2.45 GHz ISM band. An off-chiploop antenna (2.4 mm diameter) is employed for the TX that also acts asa high-Q inductive element L for the LC resonator thereby minimizingboth power consumption and the overall size of the system by eliminatingthe matching network between the TX and the antenna. The use of anactive TX also eliminates the “self-jamming” problem associated with thepassive backscattering based transmitters.

FIG. 41 depicts the energy harvesting (EH) and power managementsubsystem. In this work, the WPT leverages the cavity resonance basednear field method due to its high PTE and ability to deliver largeamounts of power to the implant. The cavity is excited by a 340-MHz RFsource. An on-chip 4-stage rectifier provides an AC-DC conversion bymultiplying the voltage induced on the receive coil. High efficiency andlow leakage Schottky diodes with forward voltage drop of <200 mV areused to implement the rectifier. The unregulated voltage V_(RECT) at theoutput of the rectifier acts as a supply voltage for the rest of thepower management circuits. Although the orientation of the coil remainsfixed once the device is implanted, an ultra-low power energy efficiencyloop is employed that tracks the V_(RECT) and tunes the capacitor bankin the on-chip matching network.

FIG. 42 shows the sub-1V and sub-1 μW BGR, which generates the pseudodifferential voltages for the R-F circuit, and reference voltages andthe 100 nA bias currents for the entire chip. The BGR generates a totalof seven precise reference voltages from 100 mV to 700 mV in steps of100 mV. The pseudo differential voltage of 100 mV is ensured by usingthree reference voltages (VR7=700 mV, VR6=600 mV, and VR5=500 mV) andusing VR6 as a common mode voltage. The difference value of a precise100 mV voltage (i.e., (VR7−VR6) and (VR6−VR5) is provided by the R-Fcircuit (section 4.5). The output reference voltage for the BGR is givenby:

$V_{RN} = {\frac{R_{N}}{R_{X}}V_{R,{Conv}}}$

where, N is from 1 to 7 in the output resistor ladder, and V_(R,Conv) isthe conventional bandgap voltage of 1.25 V. As shown in the equationabove, the generation of multiple reference voltages with a precise stepof 100 mV, in the presence of process variations, requires the multipledegrees of matching between the resistors in the BGR circuit. In orderto accomplish the task, first, we match the resistors R5, R6 and R7 witheach other by treating R6 as a “common-mode” resistor. Second, we matchthe combination of (R5+R6+R7) with the resistors R1, R2, R3, and R4.Finally, we match all the resistors RX, RZ and (RO=R1+ . . . +R7) in theBGR with each other. The matching is achieved by utilizing commoncentroid and symmetrical layout techniques. We used high density butwell-matched poly resistors to implement all the resistors in the BGRcircuit. A power-on-reset (POR) circuit pulls the gate of the PMOScurrent sources (M1-M4) down during startup. As a result, the PMOScurrent sources inject a finite amount of current into the BGR coreduring startup to ensure a stable operating point for the BGR.

The linear voltage regulators are implemented to provide a clean supplyvoltage to various blocks of the chip by regulating the unstable outputvoltage of the rectifier V_(RECT). In order to decouple the supplydomains of various circuit blocks, four separate linear voltageregulators are employed. FIG. 43 depicts the schematic diagram of thevoltage regulator and the supply voltage domains of the circuit blocks.Since an external capacitor is not available, the regulator isinternally compensated with a minimum phase margin of 57 degrees. AnNMOS pass transistor is utilized to ensure the stability across thevariable load conditions with a good power supply rejection ratio(PSRR). The reference voltage divider in the regulators consists of twoidentical PMOS transistors operating in the weak threshold region. Thesetransistors provide extremely high on-chip resistance (˜22 MΩ each) andthus consume a negligible amount of quiescent current.

A differential resistance-to-frequency (R-F) conversion is performed intwo steps: first, resistance-to-current (R-I) conversion, and second,current-to-frequency (I-F) conversion. Two separate R-F converters wereimplemented in this work for the comparison purposes. FIG. 44 shows aconcept diagram for an R-F converter, where an R-I circuit senses thedifferential change in the sensor resistance and provides an outputcurrent I_(OUT). The current I_(OUT) is then fed to the I-F converterconsisting of a current control oscillator (CCO). The CCO changes itsfrequency by sensing the current I_(OUT) and thereby providing an I-Fand hence R-F conversion.

There are two major challenges in the design of an R-I converter:linearity, and low power operation. FIG. 45 illustrates the schematicdiagram of a conventional linear R-I converter. A negative feedback loopconsisting of an op-amp, an NMOS transistor, and a sensing resistorelement, forces the voltage drop across the sense resistor to be equalto the constant reference voltage from BGR. The current generated inthis manner is highly linear and inversely proportional to the senseresistance (I_(R)=V_(REF)/R_(S)). This current is then copied to thesubsequent CCO through current mirrors (M2-M3). The power consumption ofthe circuit is dependent on the absolute values of R_(S) and V_(REF).Since the absolute base value of R_(S) is fixed, a low value of V_(REF)can be generated by the BGR to minimize power consumption. However, theminimum value of V_(REF) is limited by the dynamic range of the circuit.Thus, the power consumption of the R-I converter is mainly limited bythe absolute value of the sense resistor and the required sensitivity.

The principle of an R-I converter depicted in FIG. 45 can also beextended to differential measurements. FIG. 46 shows the schematicdiagram of the first differential R-I converter (R-I1). The differencein current I_(RS1)(=V_(REF)/R_(S1)) and I_(RS2)=(=V_(REF)/R_(S2)) isgiven by:

${I_{D} = {{I_{{RS}\; 1} - I_{{RS}\; 2}} = {\frac{V_{REF}}{R_{S\; 1}} - \frac{V_{REF}}{R_{S\; 2}}}}};\left( {R_{S\; 2} > R_{S\; 1}} \right)$

where, R_(S1) and R_(S2) are the base values of the sensor resistors atatmospheric pressure and their values are known a priori. If ΔRS is thechange in the sensor resistance with applied pressure P, then theequation 4.3 can be rearranged in accordance with equation 4.1 as:

$I_{D} = {\frac{V_{REF}}{R_{S\; 1} + {\Delta \; R_{S}}} - \frac{V_{REF}}{R_{S\; 2} - {\Delta \; R_{S}}}}$$I_{D} = {V_{REF}\left\lbrack \frac{\left( {R_{S\; 2} - R_{S\; 1}} \right) - {2\Delta \; R_{S}}}{\left( {R_{S\; 1} + {\Delta \; R_{S}}} \right)\left( {R_{S\; 2} - {\Delta \; R_{S}}} \right)} \right\rbrack}$

The term (R_(S2)−R_(S1)) is a constant difference between the basevalues of the sensor resistances, when the pressure is not applied. Thechange in resistance ΔR_(S) with applied pressure is small compared tothe absolute base values of the sense resistors (i.e. ΔR_(S)<<R_(S1,2)).Moreover, the absolute values of the sense resistances are close to eachother and are of the same order. For instance, the approximate values ofthe Volcano pressure sensor used in this work has R_(S2)=3.6KΩ andR_(S)=3.3KΩ at atmospheric pressure. The maximum change in differentialresistance ΔR_(S) is 12Ω across the IOP range (0-60 mmHg). Therefore,the equation can be written as:

$I_{D} = {V_{REF}\left\lbrack \frac{\left( {R_{S\; 2} - R_{S\; 1}} \right) - {2\Delta \; R_{S}}}{R_{S\; 1}R_{S\; 2}} \right\rbrack}$I_(D) = I_(DS, Const) − Δ I_(DS)

Here, the difference current ID has two parts: a constant currentI_(D,Const) and the change in the current ΔI_(DS) with the change insensor resistance with applied pressure. These two parts are given as:I_(DS,Const)=V_(REF) [(R_(S2)=R_(S))/R_(S2)R_(S1)], and ΔI_(DS)=V_(REF)[2ΔR_(S)/R_(S2)R_(S1)].

Both of the operational transconductance amplifiers (OTA) in the R-I1converter were identical with a high open loop gain of 100 dB. Atwo-stage miller-compensated OTA was designed for very low power, noise,and offset. Both of the OTAs were matched together to further reduce theeffect of an offset between two current branches. A 100-mV referencevoltage V_(REF) is chosen as a tradeoff between minimum powerconsumption and maximum dynamic range across the pressure range. A fullscale dynamic range of 70 nA is achieved in the ΔI_(D).

Since an R-I₁ converter uses two current branches to sense differentialresistance, high power consumption is inevitable with such a structure.A 50% power saving can be achieved with the use of only one sensingcurrent branch to measure the differential current. To accomplish thetask, a second R-I₂ converter is proposed in this work. The schematic ofthe R-I2 converter is depicted in FIG. 47.

Three negative feedback loops are introduced in the R-I₂ converter. Apseudo-differential reference voltage V_(REF) of 100 mV is generated bythe BGR as explained earlier (V_(REF)=VR₇−VR₆=VR₆−VR₅). The first andsecond feedback loop (depicted as 1 and 2 in the FIG. 47) set thereference voltages of VR7=700 mV and VR5=500 mV at the nodes “X” and“Y”, respectively, and are designed with a high loop gain (>95 dB). Thethird feedback loop sets the common-mode reference voltage of VR6=600 mVat node “N”. As a result, each resistor in the sensor sees a voltagedrop of 100 mV across it. The difference current AID flows through thetransistors M3 and M4, which is copied via current mirrors M4-M5. Sincethe third feedback loop sees both first and second loops as a load, ithas a lower loop gain (>70 dB) compared to the other two feedbacks. Thefirst and second feedback loops are designed with lower settling timethan the third feedback loop, to ensure accurate startup and stability.All of the OTAs are matched with each other in a single block to reducethe effect of offset voltages. In the calibration mode, the on-chip baseresistors (RB1,2) are switched to the feedback loop via the analogmultiplexers and the sensor resistor elements are switched to theground.

The I-F converter consists of a wide tuning range ring oscillator asdepicted in FIG. 48. A current starved inverter and a transmission gateconstitute a single-stage of the ring oscillator. The bias voltage (VBPand VBN) generated by the R-I converter controls the oscillationfrequency of the ring oscillator by regulating the resistance of thetransmission gate (RT). The oscillation frequency f_(osc) for the widetuning range N-stage ring oscillator is given by:

$f_{OSC} = \frac{_{m}}{2{{NC}_{P}\left( {1 + {_{m}R_{T}}} \right)}}$

where, g_(m) is the total effective transconductance of a single stageinverter, N is the total number of stages, and C_(P) is the totalparasitic capacitance at the gate of a single stage inverter thatconsists of the total gate capacitance of the PMOS and NMOS transistorsand the wiring capacitance.

For g_(m)R_(T)>>1, the prior equation can be rearranged as:

$f_{OSC} = \frac{1}{2{NC}_{P}R_{T}}$

The average value of Vds/I_(T) provides the effective resistance of thetransmission gate R_(T), where V_(ds) and I_(T) are the voltage drop andcurrent across the transmission gate, respectively. ForV_(dsat)<V_(DD)/2, I_(T) remains constant when a step-input rises fromV_(DD)/2 to V_(DD) and R_(T) can be approximated as:

$R_{T} = {{\frac{2\; \ln \; 2}{V_{DD}}{\int_{V_{DD}/2}^{V_{DD}}{\frac{V}{I_{T}}{dV}\frac{3\; \ln \; 2}{4}\frac{V_{DD}}{I_{T}}}}} \approx \frac{V_{DD}}{2I_{T}}}$

By combining equations, the oscillation frequency f_(osc) of the I-Fconverter is given by:

$f_{OSC} = \frac{I_{T}}{{NC}_{P}V_{DD}}$

Since the current through the transmission gate I_(T) is controlled bythe bias volt-ages VBP and VBN, generated by the R-I converter, f_(osc)is a linear function of the difference current I_(D) (I_(T)=I_(D)). Inorder to make this function extremely linear, the inverters in theconventional wide tuning ring oscillators are made current starved withthe current ID. This also minimizes the crowbar current of theinverters, and hence reduces the voltage droop in the output of acapacitor-less voltage regulator, which provides a clean supply to theoscillator. High-VTH transistors were used for the inverters, whichfurther reduces its crowbar current.

Although the temperature effect is canceled out in the differentialcurrent due to the sensor properties, it can change the absolute basevalue of the oscillation frequency. Similarly, the supply variation inthe regulated output can alter the oscillation frequency and thereforethe accuracy of the measurement. Temperature variation for the bladderpressure monitor system is not a concern, since the temperature insidethe bladder remains virtually constant.

If implanted in a physical environment with varying temperature, theimpact can be combatted or mitigated by using two on-chip base resistors(R_(B1) and R_(B2)), with values close to the absolute base values ofthe sense resistors and with the same initial resistance difference, areimplemented with n+ diffusion resistors. The n+ diffusion resistor has apositive temperature coefficient very close to the sense resistor in thetemperature range of interest. Since both the resistors values are closeto each other, a near perfect matching is achieved by laying them out ina common centroid fashion. The difference current in the base resistancesensing mode depends only on the temperature and supply variations andis utilized to calibrate the variations in the pressure sensing mode.Since the resistances of both the sensor resistors change by the sameamount with a temperature change, a difference current is given bysetting ΔR_(S) equal to zero in equation:

$I_{D} = {I_{{DS},{Const}} = {V_{REF}\left\lbrack \frac{R_{S\; 2} - R_{S\; 1}}{R_{S\; 2}R_{S\; 1}} \right\rbrack}}$

Similarly, a difference currant in the base sensing mode is given by:

$I_{D} = {I_{{DB},{Const}} = {V_{REF}\left\lbrack \frac{R_{B2} - R_{B\; 1}}{R_{B\; 2}R_{B\; 1}} \right\rbrack}}$

By dividing equation 4.12 by equation 4.13, we get:

$\frac{I_{{DS},{Const}}}{I_{{DB},{Const}}} = {{\left( \frac{R_{S\; 2} - R_{S\; 1}}{R_{B\; 2} - R_{B\; 1}} \right)\frac{R_{B\; 2}R_{B\; 1}}{R_{S\; 2}R_{S\; 1}}} = \frac{f_{{OSC},}S}{f_{{OSC},}B}}$

The resistances in the above equations are absolute base values andtheir values are known a priori. Since the sensor and base resistorsshare the same oscillator for R-F conversion, the ratio of theirfrequencies f_(osc,S)/f_(osc,B) is independent of V_(DD), as suggestedby equation 4.11. Therefore, an initial calibration for temperature andsupply voltage variation can be easily achieved by having a separatetime slot for the on-chip differential base resistance sensing mode. Adifferential sensing and an on-chip base resistor calibration method inthis work enable accurate pressure measurements without having an extratemperature, voltage and current sensing mode.

The values of the sensor and base resistors frequencies are calculatedby the counter-based digital core logic, operating at a constantreference frequency f_(REF). A similar oscillator to the one being usedin the I-F conversion but with more stages, is employed to generate amuch lower reference frequency (f_(REF)=1.5 KHz). A temperatureindependent constant bias current is utilized for the referenceoscillator. The much lower clock speed (f_(REF)) for the digital coreminimizes its dynamic power consumption and reduces the OOK data ratefor the TX.

FIG. 49(a) shows the block diagram of the digital core which providesfrequency-to-digital (F-D) conversion and encodes the resulting data fora burst transmission. The F-D converter in FIG. 49(b) consists of twocounters CNT_(SEN) and CNT_(REF). When receiving the Start signal fromthe timer, both counters are reset and start counting upward. OnceCNT_(REF) reaches 350 cycles, the conversion is completed with an end-ofconversion (EoC) pulse stopping both counters and the value of CNT_(SEN)(Data) is read out, which guarantees a minimum frequency resolution of(1 bit)/(5 Hz) at a reference clock (CLK_(REF)) frequency of 1.5 KHz.The CNT_(REF) and CNT_(SEN) are designed for 10 and 18 bits,respectively, to avoid overflow in both the counters at maximum inputclock (CLK_(IN)) frequency.

FIGS. 49 (c) and (d) show the block and state diagram of the encoder(ENC), respectively. Initially in the SLEEP state, the output of theencoder PKTO is fixed at logic “0” to turn off the TX. When receiving anEoC pulse, the encoder latches data from the F-D converter and proceedsto the next state based on the input signals DIFRS and SELRS, asindicated in FIG. 49 (d). In the SAMP RB and SAMP RS state, in which thedigital outputs generated from the reference base resistor (RB) andsensing resistor (RS), respectively are recorded, the data from the F-Dconverter is directly stored into the sampling parallel-to-serialregister (P 2SR SAMP) with 18-bit precision. While in the DIF F RSstate, where only the RS difference is stored, the P 2SR SAMP isdisabled from writing to hold the value stored in SAMP RS states.Meanwhile, the RS difference is calculated by subtracting the data withthe previously recorded RS and stored into the differentialparallel-to-serial register (P 2SR DIFF). Considering a 10-kHz dynamicrange of CLKIN, the precision of the P 2SR DIFF is set to 12 bits. Theflip-bit generator (FB Gen) counts the number of logic “1” in all thethree states via bitwise summing of the parallel data DatP. If thesummed value is greater than a threshold value, set at 9 for 18-bitdigital data and 6 for 12-bit difference, each bit of DatP is reversedand the flip-bit register (FB) is updated to logic “1”. In the nextcycles, the encoder enters either the SRL PKSAMP state where the datastored in P 2SR SAMP is serially outputted in sample packets (PKSAMP),or the SRL PKSAMP state where the RS difference stored in P 2SR DIFF isserially outputted in differential packets (PKSAMP). At the same time, a3-bit cyclic redundant check (CRC) code is also derived from the DatS.The encoder returns to the SLEEP state after the formation of the datapacket and waits for the next EoC pulse.

FIG. 50 illustrates the timing diagram of the digital core andstructures for both the sample packet (PKSAMP) and the differentialpacket (PKDIFF). The PKSAMP consists of a 4-bit header (HB) indicatingthe starting of a specific packet, a flip bit (FB), 18-bit data, a 3-bitCRC code, and a 4-bit tail (T B) indicating the ending of a packettransmission. The structure of the PKDIF F is similar to that of thePKSAMP except having a 12-bit RS difference data instead of 18-bits. Theheaders of PKSAMP transmitting the data from RB and RS are set as “1001”and “1010”, respectively, and that of PKDIF F is set as “1100”. Thetimer of the digital core is implemented with a packet counter, which,upon receiving an EoC pulse, is incremented by 1 and reset when itsvalue is equal to (NPKC−1), where NPKC is the number of packets percycle and is set to be equal to 10. As shown in FIG. 50, the Start pulsefor the F-D launches two CLKREF cycles after both EoC andreset-digital-core (RSTDC) pulses, allowing CLKIN of the F-D converterto stabilize before the conversion starts. Both the SELRS and the DIFRSsignals are disabled when the packet counter is reset, and become activehigh when the value of the packet counter is greater than 0 and 1,respectively. As a result, among the NPKC packet outputs (PKTO), the 1stand 2nd ones are PKSAMP recording the digital data converted from RB andRS, and the rest of the 8 packets are PKDIF F recording RS differences,each of which is separated by 352 CLKREF cycles. At the receiver, theexact values of RS can be recovered at 18-bit precision by summing RSdifferences with the Data obtained from the 2nd PKSAMP. Therefore, byapplying differential encoding and bit-flipping strategies to data fromthe slow-varying IOP and bladder pressure signals, the number of bit “1”in data packets and hence the switching-ON rate of OOK TX can beminimized without degrading the sampling rate and data precision, savingoverall power dissipation dominated by the TX during the datatransmission phase.

Real-time pressure monitoring with a limited amount of harvestedwireless energy requires a very low, both instantaneous and average,power consumption for the transmitter. In this work, an OOK modulated,2.45 GHz ISM band, transmitter was designed for wireless transmission ofthe data packets. FIG. 51 shows the schematic of the transmitter thatcomprises a LC voltage controlled power oscillator (VCPO). The design ofthe TX is inspired by the recent works published in [150], [151].However, in these studies, especially in [151], the TX was aggressivelyoptimized for extremely low data rate (˜1 bps) applications, where theminimization of the leakage current and the supply voltage scaling arethe two major design criteria. In this work, the design of the TX wasmainly aimed towards the reduction of both instantaneous and averagepower consumption. A 2.45 GHz ISM band was chosen for the carrierfrequency as a trade-off between power dissipation, antenna efficiency,and tissue losses. An off-chip loop antenna, with a diameter of 2.4 mm,is fabricated on the printed circuit board (PCB) that connects directlyto the VCPO at nodes X and Y. Since the circumference of the loopantenna is much smaller than its transmitting wavelength at 2.45 GHz, itconsidered an electrically small antenna. The equivalent lumped circuitmodel of an electrically small loop can be represented as a seriescombination of an inductor (LA) and a small resistor (RA) as can be seenin FIG. 52. Therefore, an off-chip electrically small loop caneffectively be utilized as the inductive element for the LC tank circuitof the VCPO. The self-resonance frequency of the loop antenna istypically much higher than the resonance frequency of the LC tank andcan be modeled by adding a parallel capacitor CSRF.

The design of the antenna is optimized to maximize its radiationefficiency and minimize the tissue losses in an implantable environmentfor the given size constraints (Table 4.1). It is a well-known fact thatthe radiation efficiency of an antenna increases with its physical sizeor carrier frequency (since the carrier wavelength approaches thephysical dimension of the antenna). However, tissue conductivity alsoincreases with frequency, resulting in higher tissue losses. In order toefficiently utilize the space available for the implant, a diameter of2.4 mm was chosen for the loop antenna. A carrier frequency of 2.45 GHzoffers a good balance between the radiation efficiency and tissuelosses. The antenna was designed and optimized using the full-wave 3-Delectromagnetic simulation software ANSYS High Frequency StructuralSimulator (HFSS). The antenna parameters with HFSS simulations arelisted in Table 4.2.

TABLE 4.2 HFSS simulation and calculation results for the loop antenna Lwith Antenna Calculated Simulations wirebond Gain Efficiency @ 2.45 GHzL (nH) (nH) (dB) (%) Q 20 μm thick Parylene 4.87 6.4 −21.57 1.47 121substrate with 20 μm Parylene coating layer Gold trace on 20 μm 4.886.41 −22.86 1.27 91 Parylene substrate with a coating layer FR-4 board4.75 6.27 −19.9 1.47 172 (Air)

FIGS. 53(a) and (b) show the simulated radiation pattern for the loopantenna, designed on a FR-4 PCB and a parylene substrate, respectively.

FIG. 51 shows the schematic diagram of the VCPO. The core of theoscillator consists of the NMOS (M1-M2) and PMOS (M3-M4) cross-connectedtransistor pairs, an LC tank circuit, and a tail current source NMOStransistor M5. Having both the PMOS and NMOS cross-couple pairsincreases the effective transconductance of the VCPO, thereby reducingthe startup current required for the VCPO to ensure oscillations. Thisconfiguration also discards a need for center tapping the loop antennato bias the VCPO, thereby simplifying final device packaging which isessential in the IOP monitor system. The sizes of the transistors M1-M4are designed carefully to minimize the phase noise, while ensuring anacceptable start-up condition for the VCPO [152]. Additional powersaving during startup is achieved by using a high-Q inductive elementfor the LC tank circuit, which is implemented by an off-chip loopantenna.

The data packets from the digital core directly OOK modulate the TX bydynamically switching the tail current source transistor M5. The size ofthe transistor M5 is chosen such that the VCPO delivers 80 μW (−11 dBm)of instantaneous power to the loop antenna. The TX is operated at aregulated supply voltage of 1.2 V. The TX was simulated with extractedlayout parasitics and extracted s-parameters of the antenna from HFSSsimulations. With no on-chip tuning capacitor, the maximum frequency ofthe VCPO is limited by the parasitic capacitances at node X and Y(mainly due to the bond-pad and device capacitances). The extractedsimulations in the Cadence R Spectre R RF result in the maximum VCPOoscillation frequency of 3.4 GHz without the tuning capacitors. Thus, aMetal-Insulator-Metal (MIM) capacitor was introduced in the LC tankcircuit to obtain a carrier frequency at 2.45 GHz ISM Band (2.4 GHZ-2.5GHz).

Since the TX design is extremely power efficient, it can be useful invarious other short-range biomedical communication applications, such asa wireless body area network (WBAN). Therefore, the design of this TX isalso optimized as a separate stand-alone structure. A 5-bit capacitiveMIM DAC is implemented to provide a tuning range from 2.3 GHz-2.7 GHz,as depicted in FIG. 54. This tuning range would also cover a 2360MHz-2400 MHz frequency band allocated for WBAN (IEEE 802.15.6) [153].Unlike the digital switch implemented in [151], this work utilizes aresistor based switch biasing scheme [154] that provides a definiteoff-state negative gate-to-source voltage Vgs for the NMOS switchdepicted in FIG. 54. A frequency-shift-keying (FSK) modulation withvariable bandwidth is also possible by dynamically switching the DACtuning capacitors via data packets. In order to reconfigure the outputpower delivered, seven tail current sources M5<6:0> with binary weightedsizes are employed.

The pressure sensing readout ASIC is implemented and fabricated in astandard 0.18 μm CMOS process. The chip occupies 750 μm×750 μm ofsilicon area, including bond pads. The microphotograph of the chip isillustrated in FIG. 55. Since the full system SoC has a limited numberof testing bond pads due to the size restriction, separate teststructure dies were fabricated to characterize the individual circuitblocks. First, the DC testing of the individual circuit blocks wasperformed. The pressure sensor resistor is placed in the pressurechamber to carry out the measurements. The pressure in the chamber isvaried from 0 mmHg to 60 mmHg and the variation in difference current IDis measured for both R-I1 and R-I2 circuit blocks (FIG. 56). The dynamicrange of ID was measured to be 105 nA across the pressure range of 0-60mmHg, which is very close to the simulated value. FIG. 57 (a)illustrates the pseudo-differential reference voltage across the sensorresistor terminals for the R-I2 converter. The voltage drop across boththe sensing elements was precise and measured to be 100 mV, as can beseen in Figure. Similarly, the voltage drop across the sensing elementsin R-I1 converter was accurately measured to be 100 mV (FIG. 57 (b)).

The output voltages of the all four voltage regulators are measured tobe within ±3% of the designed values across multiple dies. The measuredbias current of the chip is 97 nA, which is very close to the designedvalue of 100 nA.

A TX test structure allowing frequency and current tuning is used tocharacterize its performance. A loop antenna with 2.4 mm diameter isfabricated on a FR4 printed circuit board (PCB). The TX die is directlywire-bonded to the antenna trace in order to minimize the effect ofparasitics. Since the loop antenna is directly connected to the nodes Xand Y of the VCPO (FIG. 51) and no buffers or PA were implemented, adirect probing of the TX output was not possible. Therefore, all themeasurements for the TX are done in a wireless test setup. A hornantenna with a gain 8 dBi is placed approximately 20 cm away from the TXchip. The horn antenna is connected to the Agilent E4404B spectrumanalyzer, which receives the transmitted data. A value −52 dBm of thepeak power was received with this setup. With the help of the well-knownFriis transmission formula for the received power, the peak output powerof the TX is calculated to be −33.76 dBm. The VCPO power consumption forthis setup was measured to be 69.8 μW (=−11.56 dBm), providing loopantenna gain of −22.2 dB.

FIG. 58 depicts the output spectrum of the TX, OOK modulated by apseudo-random-binary-sequence (PRBS) at 1 Mbps, 5 Mbps and 10 Mbps datarates. Although the TX is not designed to provide a FSK modulation, thefuture revision of this design can easily accommodate a sub-DACcapacitive array to enable FSK modulation along with the course tuningarray which is already implemented in this chip. To demonstrate thepossibility of FSK modulation, the minimum capacitor of 43 fF in thetuning DAC array is switched with a 1 Mbps PRBS data, resulting in awide-band FSK spectrum depicted in FIG. 59. The transmitter consumes 140μW in this mode. The VCPO achieves a phase noise of −115 dBc/Hz at anoffset of 1 MHz from the carrier frequency.

Next, full system testing is carried out by placing the sensing elementin a pressure chamber. The sensing element is connected to the R-Iconverter of the chip. The full system SoC employs the R-I2 converterdue to its low power feature. The digital core sends the Sel RS signalto the R-I2 converter to select either the sensing element or theon-chip base resistor (Sel RS=0 selects the sensing element and Sel RS=1selects base resistance). The measured output frequency of the R-Fcircuit corresponding to the on-chip base resistance was 360 KHz. FIG.60 shows the measured periodic Sel RS signal, R-F converter output,reference oscillator clock, and digital data packets at a constantpressure. The measured data packets for the base frequency (30 bits),sensing element frequency (30 bits), and difference frequency (24 bits)are illustrated in FIG. 61. The header bits (HB) are different for allthree types of packets for decoding purposes, as can be seen in thefigure.

FIG. 62 depicts the measured sensor and base frequencies within thepressure range of interest. The sensor frequency ranges from 390.7 KHzto 379.9 KHz, resulting in the resolution of 0.024 mmHg/LSB with thedigital core counter conversion time of 350 reference clock cycles at1.5 KHz. However, the actual sensor resolution is limited by thethermal-noise. The thermal noise of the op-amps in the R-I convertercircuit is the dominant noise source in the readout chip due to theirlow power dissipation. The noise simulation of the R-I convertersuggests an rms error of 0.31 (mmHg)rms in the pressure readout. Themeasured value of the average base resistor frequency remains constantat 360 KHz.

A sensing resistance dynamic range of 12Ω was measured with the Agilent4284A Precision LCR meter for the pressure range of 0-60 mmHg. Maximumnon-linearity is measured to be 87 mΩ with the two-point calibration,resulting in the readout sensitivity of 0.44 mmHg. The measured sensingresistance linearity is depicted in FIG. 63 for the nominal differencein sensor resistances (RS1-RS2) of 312Ω. This sensitivity is enough toaccommodate both the IOP and the bladder pressure range. The rms errorcan be reduced by either increasing the conversion time or averaging themultiple data samples taken at each pressure point. FIG. 64 shows theimprovement in the measured sensitivity when the number of data samplesto be averaged are increased.

Next, the SoC was measured in a wireless setup. A 2-turn, 100 μm thick,receive powering coil of 2.6 mm diameter is connected in front of theon-chip matching network. The sensor is placed in the pressure chamberand the system is kept in a cavity resonator which is excited by a 340MHz RF source. The data is received by a spectrum analyzer anddemodulated by the base-station comprises of commercial-off-the-shelf(COTS) components. FIG. 65 depicts the output power spectrum of thereceived data packets. Demodulated data packets are then fed to a FPGAboard which has an UART interface to a computer. The received datapackets are decoded real-time in the matlab software. FIG. 66 shows thereceived data by a spectrum analyzer and corresponding digital packets,demonstrating correct packet reception.

Since the sensitivity of the pressure sensing chip is mainly limited bynoise, it is important to characterize it in a wireless setup. FIG. 67shows deviation due to noise in the wirelessly measured data at aconstant pressure. A total of 60 data packets were averaged for eachnoise measurement. FIG. 68 depicts the resulting histogram forwirelessly measured noise. The standard deviation (1σ) is measured to be429.12 ppm, or 133.9 mΩ for a nominal difference in sensor resistancesof 312Ω, resulting in a pressure sensitivity of 0.67 mmHg. FIG. 69depicts the wirelessly measured pressure with time and compares it witha reference sensor. After the 2-point calibration, the maximum measurederror in the pressure reading was 0.81 mmHg with a standard deviation of0.63 mmHg.

Temperature effects on the sensing and base frequencies were alsocharacterized and the results are depicted in FIG. 70. The maximum errorin the recorded pressure due to temperature variation was measured to be0.54 mmHg, after performing a 2-point calibration in the temperaturerange of 30° C. to 38° C. With a 3-point calibration, the error in thepressure measurement due to temperature is further reduced to 0.39 mmHg.

Thanks to the burst data transmission, the chip consumes 61.4 μW fromthe harvested energy. Table 4.3 illustrates the measured performancesummary of the ASIC.

TABLE 4.3 Performance Summary Process node 0.18 μm Unregulated supply1.35 V Power consumption 61.4 μW Rectifier Efficiency 15.35% PowerTransfer  4.3% Efficiency (PTE) Difference resistance 133.9 mΩ (1σ)resolution Pressure resolution 0.67 mmHg (1σ)

The performance comparison of the ASIC with the previously publishedpressure monitor systems is presented in Table 4.4.

TABLE 4.4 Comparison with previous work [127] [42] [108] [41] This WorkJSSC′11 TbioCAS′10 TCAS1′13 JSSC′01 Unregulated Supply 1.35 V 1.5 V >1.5V — >3 V Voltage Regutated Supply 1.2 V, 1 V 1.5 V 3.6 V 3 V VoltageEnergy Harvesting MRC/Cavity RF RF Battery Inductive Source ResonatorEnergy Harvesting 340 MHz-434 MHz 2.4 GHz 3.65 GHz — 13.56 MHz FrequencySensor Resistive Capacitive Capacitive Capacitive Capacitive(differential) Full System ✓ ✓ ✓ x ✓ (Wireless) TX Frequency 2.45 GHz2.4 GHz 2.4 GHz — 13.56 MHz TX P_(out) −33.8 dBm N/A −45 dBm — N/A TXData Rate 1.5 Kbps/ 21-25 kbps 8 Mbps — 26.5 kbps 103 bps (Burst)Modulation OOK Backscatter OOK FSK Backscatter Pressure Resolution 0.67mmHg 0.9 mmHg 1.27 mmHg 0.5 mmHg^(‡) 0.73 mmHg* (9-bit) Power Power 2.1μA 1.041 μW 39.38 μW 116.9 nW N/A Management Readout 39.37 μA 1.19 μW158.91 μW 7 μW N/A Front End TX 5.4 μW — 1.1506 mW 47 mW — (6.86%) TotalPower 61.4 μW 2.3 μW 1.3533 mW N/A 210 μW^(†) CMOS Technology 0.18 μm0.13 μm 0.13 μm 0.18 μm 1.2 μm Chip Area 0.75 × 0.75 mm² 1 × 0.7 mm² 0.7× 0.7 mm² 1.8 mm² 6.76 mm² Micro-system 0.78 mm^(3††) N/A N/A 1.5 mm³N/A Volume ^(‡)Resolution is not measured for fully wireless system.*Converted to mmHg from given pressure range and resolution of 9-bits,^(†)power consumption from regulated supply, ^(††)After the chipback-lapping process.

Finally, the ASIC performance was evaluated in the in-vivo rodentexperiment. The bladder pressure was recorded from an anesthetized rat.Since the pressure sensor die was packaged with three long leadsconnected to it, implantation of the entire microsystem inside the rat'sbladder was not possible in this experiment. Therefore, the pressuresensor was implanted inside the bladder and connected to the ASICmicrosystem that is kept outside the animal. However, in future, themicrosystem can be fully implanted, when the lead-less bare dies willavailable for the pressure sensor. FIG. 71 (a) illustrates theexperimental setup. The pressure response of the bladder to infusion ofsaline into the bladder, at a constant rate of 4 ml/Hour, is recordedand depicted in FIG. 71 (b).

Through the aspects described herein, a low-power, sub-mm3 IOP andbladder pressure monitoring microsystem is presented in this disclosure.The microsystem can be implanted in any of a variety of anatomicalsetting suitable for pressure measurements, including but not limited tothe bladder of a mammalian subject. The microsystem integrates apressure sensor, a powering coil, a loop antenna and a low-powerwireless pressure readout ASIC in a given space of 2.6 mm diameter.Thanks to the low power pressure sensing front-end, power management,and transmitter circuitry, the power consumption of the chip is only61.4 μW, while harvesting the energy wirelessly form a 340 MHz RF sourcethrough a cavity resonator.

Cavity Resonator

FIG. 72 illustrates a cavity resonator forming part of the wirelesspower transfer system for use with pre-clinical studies involvingcertain non-human mammals (e.g. rats, pigs, rabbits, etc. . . . ), suchas is common in the field of medical research. The cavity resonatordescribed with regard to FIGS. 72-74 can be used in combination with thedevices, systems, assemblies, methods, and techniques describedthroughout this document. The resonant cavity is sized and dimensionedto receive one or more such mammals (e.g. the rat shown in FIG. 72)after it has been surgically implanted with a Bionode at a givenlocation for a given topic of study (e.g. epilepsy, etc. . . . ). Inuse, the resonant cavity is excited in TM110 mode characterized bycirculating magnetic fields (red=high; blue=low). An untethered animalwith an implanted, packaged Bionode device is housed within the cavityvolume. A bi-axial arranged receive coil system on the Bionode device isutilized to achieve orientation insensitivity for continuous powercoupling.

FIG. 73 illustrates a constructed cavity resonator and fully assembleddevice with Bionode microelectronics platform, power management board,and receive coil assembly according to the present disclosure. In thisarrangement, the magnetic field source is the cavity itself, which isconstructed from any of a variety of suitable metallic materials (e.g.aluminum). Optimal impedance matching is used to tune the system andattain maximum power transfer efficiency to the Bionode implanted withinthe untethered animals in or near the resonant cavity. The cavity mayhave any suitable dimension, but in one example was constructed withcavity dimensions of 60 cm×60 cm×30 cm, providing a large operatingvolumetric space (˜1e5 cm3). A biaxial receive coil system (disposed inthe implanted Bionode) includes two copper coils with any suitabledimension, such as (but not limited to) diameters of 5 mm and 7 mm.

The resonant cavity system described herein boasted greater than 90%continuous device powering of 6 freely behaving, untethered rats, with apeak power transfer efficiency of 14.3%. The resonant cavity systemmaintains sufficient wireless power transfer performance to afreely-behaving rodent in a large operational volume. The resonantcavity system achieves a power transfer efficiency (PTE) levelsufficient to safely operate a power-demanding (>40 mW), multi-featuredimplantable device. FIG. 74 illustrates a comparison of the wirelesspower transfer performance of the resonant cavity system relative toother types of wireless power transfer.

Based on these collective features, the resonant cavity system of thisdisclosure provides significant promise for the field of pre-clinicaltesting involving the use of non-human mammals, such as describedherein. By providing the wireless power transfer to untethered animals,industry may maximize the efficiency and scale of biomedical researchinvolving implanted Bionodes. This, in turn, may hasten the adoption andproliferation of Bionodes for the treatment in human or veterinarypatients of a host of diseases or pathologies that would otherwise relyprimarily (and oftentimes exclusively) on pharmacologic treatmentoptions.

Embodiments of the subject matter and the functional operationsdescribed in this specification can be implemented in digital electroniccircuitry, or in computer software, firmware, or hardware, including thestructures disclosed in this specification and their structuralequivalents, or in combinations of one or more of them. Embodiments ofthe subject matter described in this specification can be implementedusing one or more modules of computer program instructions encoded on acomputer-readable medium for execution by, or to control the operationof, data processing apparatus. The computer-readable medium can be amanufactured product, such as hard drive in a computer system or anoptical disc sold through retail channels, or an embedded system. Thecomputer-readable medium can be acquired separately and later encodedwith the one or more modules of computer program instructions, such asby delivery of the one or more modules of computer program instructionsover a wired or wireless network. The computer-readable medium can be amachine-readable storage device, a machine-readable storage substrate, amemory device, or a combination of one or more of them.

The term “data processing apparatus” encompasses all apparatus, devices,and machines for processing data, including by way of example aprogrammable processor, a computer, or multiple processors or computers.The apparatus can include, in addition to hardware, code that creates anexecution environment for the computer program in question, e.g., codethat constitutes processor firmware, a protocol stack, a databasemanagement system, an operating system, a runtime environment, or acombination of one or more of them. In addition, the apparatus canemploy various different computing model infrastructures, such as webservices, distributed computing and grid computing infrastructures.

A computer program (also known as a program, software, softwareapplication, script, or code) can be written in any form of programminglanguage, including compiled or interpreted languages, declarative orprocedural languages, and it can be deployed in any form, including as astand-alone program or as a module, component, subroutine, or other unitsuitable for use in a computing environment. A computer program does notnecessarily correspond to a file in a file system. A program can bestored in a portion of a file that holds other programs or data (e.g.,one or more scripts stored in a markup language document), in a singlefile dedicated to the program in question, or in multiple coordinatedfiles (e.g., files that store one or more modules, sub-programs, orportions of code). A computer program can be deployed to be executed onone computer or on multiple computers that are located at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

The processes and logic flows described in this specification can beperformed by one or more programmable processors executing one or morecomputer programs to perform functions by operating on input data andgenerating output. The processes and logic flows can also be performedby, and apparatus can also be implemented as, special purpose logiccircuitry, e.g., an FPGA (field programmable gate array) or an ASIC(application-specific integrated circuit).

Processors suitable for the execution of a computer program include, byway of example, both general and special purpose microprocessors, andany one or more processors of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read-only memory ora random access memory or both. The essential elements of a computer area processor for performing instructions and one or more memory devicesfor storing instructions and data. Generally, a computer will alsoinclude, or be operatively coupled to receive data from or transfer datato, or both, one or more mass storage devices for storing data, e.g.,magnetic, magneto-optical disks, or optical disks. However, a computerneed not have such devices. Moreover, a computer can be embedded inanother device, e.g., a mobile telephone, a personal digital assistant(PDA), a mobile audio or video player, a game console, a GlobalPositioning System (GPS) receiver, or a portable storage device (e.g., auniversal serial bus (USB) flash drive), to name just a few. Devicessuitable for storing computer program instructions and data include allforms of non-volatile memory, media and memory devices, including by wayof example semiconductor memory devices, e.g., EPROM (ErasableProgrammable Read-Only Memory), EEPROM (Electrically ErasableProgrammable Read-Only Memory), and flash memory devices; magneticdisks, e.g., internal hard disks or removable disks; magneto-opticaldisks; and CD-ROM and DVD-ROM disks. The processor and the memory can besupplemented by, or incorporated in, special purpose logic circuitry.

To provide for interaction with a user, embodiments of the subjectmatter described in this specification can be implemented on a computerhaving a display device, e.g., LCD (liquid crystal display), OLED(organic light emitting diode) or other monitor, for displayinginformation to the user and a keyboard and a pointing device, e.g., amouse or a trackball, by which the user can provide input to thecomputer. Other kinds of devices can be used to provide for interactionwith a user as well; for example, feedback provided to the user can beany form of sensory feedback, e.g., visual feedback, auditory feedback,or tactile feedback; and input from the user can be received in anyform, including acoustic, speech, or tactile input.

The computing system can include clients and servers. A client andserver are generally remote from each other and typically interactthrough a communication network. The relationship of client and serverarises by virtue of computer programs running on the respectivecomputers and having a client-server relationship to each other.Embodiments of the subject matter described in this specification can beimplemented in a computing system that includes a back-end component,e.g., as a data server, or that includes a middleware component, e.g.,an application server, or that includes a front-end component, e.g., aclient computer having a graphical user interface or a Web browserthrough which a user can interact with an implementation of the subjectmatter described is this specification, or any combination of one ormore such back-end, middleware, or front-end components. The componentsof the system can be interconnected by any form or medium of digitaldata communication, e.g., a communication network. Examples ofcommunication networks include a local area network (“LAN”) and a widearea network (“WAN”), an inter-network (e.g., the Internet), andpeer-to-peer networks (e.g., ad hoc peer-to-peer networks).

While this specification contains many implementation details, theseshould not be construed as limitations on the scope of the invention orof what may be claimed, but rather as descriptions of features specificto particular embodiments of the invention. Certain features that aredescribed in this specification in the context of separate embodimentscan also be implemented in combination in a single embodiment.Conversely, various features that are described in the context of asingle embodiment can also be implemented in multiple embodimentsseparately or in any suitable subcombination. Moreover, althoughfeatures may be described above as acting in certain combinations andeven initially claimed as such, one or more features from a claimedcombination can in some cases be excised from the combination, and theclaimed combination may be directed to a subcombination or variation ofa subcombination.

Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. In certain circumstances, multitasking and parallel processingmay be advantageous. Moreover, the separation of various systemcomponents in the embodiments described above should not be understoodas requiring such separation in all embodiments, and it should beunderstood that the described program components and systems cangenerally be integrated together in a single software product orpackaged into multiple software products.

Thus, particular embodiments of the invention have been described. Otherembodiments are within the scope of the following claims. In addition,the actions recited in the claims can be performed in a different orderand still achieve desirable results.

1.-88. (canceled)
 89. A biomodulation system comprising: an implantableassembly comprising: a control module operably connected to at least onecommunication channel and at least one stimulation output, the controlmodule comprising a processor unit to process information sensed via theat least one communication channel and, upon determining a conditionexists, to generate an output to trigger the generation of a stimulus;one or more sensors located within a subject to obtain a pH level, atemperature, and a respiratory condition; and a first electrodeconfigured to deliver the stimulus to the subject based at least in parton one or more of the pH level, temperature, and respiratory condition,wherein the stimulus is configured to affect a reflex.
 90. Thebiomodulation system of claim 89, wherein the first electrode isconfigured to deliver the stimulus to a location selected from the groupconsisting of the brain stem, cortex, vagus nerve, sympathetic nerves,upper esophageal sphincter, and larynx.
 91. The biomodulation system ofclaim 89, wherein the electrical stimulation comprises deep brainstimulation (DBS).
 92. The biomodulation system of claim 89, comprisinga non-implantable assembly comprising a data communications systemconfigured to transmit the user input to the implantable assembly. 93.The biomodulation system of claim 92, wherein the non-implantableassembly comprises a source for wireless power transfer to a powermanagement module of the implantable assembly.
 94. The biomodulationsystem of claim 93, wherein the wireless power transfer is accomplishedusing magnetic resonance coupling.
 95. The biomodulation system of claim93, wherein the wireless power transfer is accomplished using near-fieldmagnetic inductive coupling.
 96. The biomodulation system of claim 89,wherein the implantable assembly comprises a power management moduleconfigured to continuously generate operating voltage for theimplantable assembly.
 97. The biomodulation system of claim 89, whereinthe power management module generates operating voltage to supply (1)analog front-end circuitry for the at least one communication channel,(2) the processor unit, (3) bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and (4)stimulation generation circuitry.
 98. The biomodulation system of claim89, wherein the power management module generates two or more differentoperating voltages comprising one or more first operating voltages at afirst voltage level and one or more second operating voltages having asecond voltage level that is independent of the first voltage level,wherein the operating voltages supply (1) different portions of theanalog front-end circuitry for the at least one communication channel,(2) the processor unit, (3) the bi-directional telemetry component tocommunicate data to and from the non-implantable assembly, and (4) thestimulation generation circuitry, and wherein the second operatingvoltage supplies the stimulation generation circuitry.
 99. A method ofbiomodulation, comprising: monitoring a physiological pathway by anelectrode to obtain a condition measurement including a pH level,temperature, and respiratory level; wirelessly transmitting thecondition measurement to a control module of an implantable assembly,the control module implanted within the subject remote from theelectrode and operably connected to at least one communication channelconfigured to receive the condition measurement, the control modulecomprising a processor unit to process the condition measurement sensedvia the at least one communication channel; determining a conditionexists based at least in part on the condition measurement; anddelivering an electrical stimulation configured to affect a reflex. 100.The method of claim 99, wherein delivering an electrical stimulationcomprises delivering an electrical stimulation to a location selectedfrom the group consisting of the brain stem, cortex, vagus nerve,sympathetic nerves, upper esophageal sphincter, and larynx.
 101. Themethod of claim 99, comprising: wirelessly transferring the conditionmeasurement to a non-implantable assembly; processing the conditionmeasurement by the non-implantable assembly; and transmitting a commandto the implantable assembly to generate an output to deliver theelectrical stimulation.
 102. The method of claim 99, comprisingtransferring power wirelessly to a power management module of theimplantable assembly.
 103. The method of claim 102, wherein transferringpower comprises charging a rechargeable battery of the implantableassembly.
 104. The method of claim 103, comprising transferring powerwirelessly to the electrode, the wireless power transfer sufficient forthe electrode to generate the electrical stimulation.
 105. The method ofclaim 99, wherein the at least one communication channel comprises awired lead.
 106. The method of claim 99, wherein the at least onecommunication channel comprises a wireless communication channel.107.-192. (canceled)
 193. The biomodulation system of claim 89, whereinthe reflex is laryngospasm and the stimulus is configured to prevent atleast one of sudden unexplained death from epilepsy (SUDEP) or suddeninfant death syndrome (SIDS) due, at least in part, to laryngospasm.194. The method of claim 99, wherein the reflex is laryngospasm and theelectrical stimulation is configured to prevent at least one of suddenunexplained death from epilepsy (SUDEP) or sudden infant death syndrome(SIDS) due, at least in part, to laryngospasm.